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1

Dopamine depletion impairs precursor cell proliferation in Parkinson disease  

Microsoft Academic Search

Cerebral dopamine depletion is the hallmark of Parkinson disease. Because dopamine modulates ontogenetic neurogenesis, depletion of dopamine might affect neural precursors in the subependymal zone and subgranular zone of the adult brain. Here we provide ultrastructural evidence showing that highly proliferative precursors in the adult subependymal zone express dopamine receptors and receive dopaminergic afferents. Experimental depletion of dopamine in rodents

Pamela Rizk; Marie P Muriel; Charles Duyckaerts; Wolfgang H Oertel; Isabelle Caille; Etienne C Hirsch; Günter U Höglinger

2004-01-01

2

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

Microsoft Academic Search

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

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

2007-01-01

3

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

PubMed

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

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

2014-05-28

4

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.

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

2014-01-01

5

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

2007-01-01

6

Dopamine sudden depletion as a model for mixed depression.  

PubMed

Up to date research on Bipolar Disorders' phenomenology is in keeping with early descriptions made by E. Kraëpelin regarding the overlap in clinical presentation of both manic and depressive symptoms, namely, mixed states. The latter constitute a highly prevalent and characteristic clinical presentation of Bipolar Disorders' and entail therapeutic difficulties, prognostic implications and increased suicidal risk. Notwithstanding, mixed states', more specifically mixed depression, have been underestimated and bypassed to the point where currently neither diagnostic criteria nor specific therapeutic recommendations are provided. In addition to the lack of agreement on nosography and diagnostic criteria, mixed depression is usually excluded from Bipolar Disorders' neurobiological models. Furthermore, renewed interest in the role of dopamine in Bipolar Disorders' physiopathology has left aside hypothesis that may account for the aforementioned clinical presentation. Interestingly enough, other syndromes arising from sudden dopamine depletion such as neuroleptic dysphoria or withdrawal syndromes from dopaminergic drugs, bear remarkable clinical similarities with mixed depression. These syndromes have been subject of further research and may thus provide a model for mixed states' physiopathology. Indeed, this article accounts for clinical similarities between mixed depression, neuroleptic induced dysphoria, and other behavioural syndromes arising from sudden dopamine depletion. After reviewing neurochemical basis of such syndromes we present, to the best of our knowledge, the first neurobiological hypothesis for mixed depression. Specifically, such hypothesis regards over activation symptoms as auto regulatory attempts to compensate for sudden dopaminergic depletion. This hypothesis provides with a beginning step for the neglected problem of mixed depression, a non-antithetic link between the dopaminergic hypothesis for both manic and depressive symptoms, a plausible explanation regarding inter individual variability to mixed depression susceptibility, and suggests new approaches for the development of novel treatments in which dopamine dysregulation should be targeted. PMID:22036092

Strejilevich, S A; Teitelbaum, J; Martino, D J; Quiroz, D; Kapczinski, F

2012-01-01

7

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.

Schulz, Enrico; Baumkotter, Jochen; Ploner, Markus

2014-01-01

8

Qualitative changes in ultrasonic vocalization in rats after unilateral dopamine depletion or haloperidol: A preliminary study  

PubMed Central

The sensorimotor speech/voice deficits associated with Parkinson Disease have been well-documented in humans. They are largely resistant to pharmacological and surgical treatment, but respond to intensive speech treatment. The mechanisms underlying this phenomenon are not well understood and are difficult to systematically test in humans. Thus we turn to the rat as a model. The purpose of this study is to compare the ultrasonic vocalization (USV) of rats in three conditions: control, haloperidol-induced transient dopamine depletion, and unilateral 6-hydroxydopamine (6-OHDA) induced moderately-severe degeneration of dopamine neurons. It was hypothesized that both dopamine-altered conditions would lead to a change in the features of the USV acoustic signal. Results demonstrated that bandwidth decreased in the dopamine-altered rats. This is the first study to document a degradation of the acoustic signal of frequency-modulated 50-kHz calls as a result of interfering with dopamine synaptic transmission in rats. The data suggest that mild transient dopamine depletion with haloperidol or even unilateral degeneration of dopamine neurons is associated with changes in the USV acoustic signal. Thus, dopaminergic dysfunction appears to influence USV production. This study provides a foundation to examine the role of dopamine in sensorimotor processes underlying USV production and potentially to explore treatments for dopamine deficiency-related impaired vocal outcome.

Ciucci, Michelle; Ma, Teh-Sheng; Fox, Cynthia; Kane, Jacqueline; Ramig, Lorraine; Schallert, Timothy

2007-01-01

9

Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine  

Microsoft Academic Search

Previous studies have demonstrated that dopamine (DA) agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats; other reports suggest that this stimulant-induced disruption of PPI may reflect drug-induced increases in ASR amplitude rather than changes in sensorimotor gating. In the current study, 6-hydroxydopamine lesions that depleted dopamine from the nucleus accumbens,

N. R. Swerdlow; R. S. Mansbach; M. A. Geyer; L. Pulvirenti; G. F. Koob; D. L. Braff

1990-01-01

10

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

GEORGE C. WAGNER; GEORGE A. RICAURTE; LEWIS S. SEIDEN; CHARLES R. SCHUSTER; RICHARD J. MILLER; JOHN WESTLEY

1980-01-01

11

The effect of dopamine on MPTP-induced rotarod disability.  

PubMed

Dopamine depletion in Parkinson's disease (PD) results in bradykinesia and tremor. Therapeutic administration of the dopamine precursor, l-Dopa, alleviates these symptoms but dyskinesia's can manifest with chronic treatment. In the MPTP toxin mouse model of PD, lesion severity is often assessed by the rotarod behavioral assay. Dopamine depletion by MPTP is thought to induce rotarod behavioral decline. Here we surveyed rotarod behavior and striatal dopamine at timed intervals post-MPTP. Paradoxically, rotarod disability coincided with gradual striatal dopamine restoration. l-Dopa supplementation exacerbated rotarod disability, whereas dopamine antagonism restored performance. Conclusion: dopamine restoration, not depletion, precipitates rotarod disability after MPTP intoxication, and caution should be applied when using this assay for MPTP. PMID:23562518

Ayton, Scott; George, Jessica L; Adlard, Paul A; Bush, Ashley I; Cherny, Robert A; Finkelstein, David I

2013-05-24

12

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: tfujimot@med.nagoya-u.ac.jp

2006-12-08

13

Involvement of D1 Dopamine Receptors in the Nicotine-Induced NeuroEndocrine Effects and Depletion of Diencephalic Catecholamine Stores in the Male Rat  

Microsoft Academic Search

Male rats were treated acutely with nicotine (4 × 2 mg\\/kg, 30-min time intervals, total treatment time 2 h) or exposed to cigarette smoke from 4 × 1 cigarette (30-min time intervals, total treatment time 2 h). Some rats were pretreated with the Dl dopamine (DA) receptor antagonist SCH 23390 (0.1–3.0 mg\\/kg, i.p.), or with the D2 DA receptor antagonists

Kurt Andersson; Kjell Fuxe; Peter Eneroth; Anders Härfstrand; Luigi F. Agnati

1988-01-01

14

Markers of dopamine depletion and compensatory response in striatum and cerebrospinal fluid.  

PubMed

Though depletion of CSF homovanillic acid (HVA) concentration has often been regarded as a direct indicator of dopamine (DA) deficiency in Parkinson's Disease (PD), CSF HVA is normal in mildly affected patients. To explore why, we measured DA and its metabolites in striatum and CSF in rabbits receiving reserpine for 5 days. Reserpine, which depletes striatal DA by disrupting vesicular storage of the neurotransmitter, results in a compensatory increase of DA turnover. In response to a 96% depletion of striatal DA, its catabolic intermediates 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) decreased 64% and 92% in striatum, although the endproduct, HVA, was unchanged. In contrast, CSF concentrations of HVA and DOPAC increased significantly, though 3-MT and levodopa (LD) were unaltered. A 5-fold rise in striatal LD concentration after reserpine-induced DA depletion provided evidence for enhanced DA synthesis. As in PD, the compensatory increase of DA synthesis after reserpine administration confounds the ability of CSF HVA to reflect DA depletion. PMID:7605589

Loeffler, D A; LeWitt, P A; DeMaggio, A J; Juneau, P L; Milbury, P E; Matson, W R

1995-01-01

15

Homeostatic Plasticity of Striatal Neurons Intrinsic Excitability following Dopamine Depletion  

Microsoft Academic Search

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

Karima Azdad; Marcelo Chŕvez; Patrick Don Bischop; Pim Wetzelaer; Bart Marescau; Peter Paul de Deyn; David Gall; Serge N. Schiffmann; Katrina Gwinn

2009-01-01

16

Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies  

Microsoft Academic Search

Dysfunction in the monoamine systems of serotonin (5-HT), norepinephrine (NE) and dopamine (DA) may causally be related to major depressive disorder (MDD). Monoamine depletion studies investigate the direct effects of monoamines on mood. Acute tryptophan depletion (ATD) or para-chlorophenylalanine (PCPA) deplete 5-HT, acute phenylalanine\\/tyrosine depletion (APTD) or alpha-methyl-para-tyrosine (AMPT) deplete NE\\/DA. Available depletion studies found conflicting results in heterogeneous populations:

H G Ruhé; N S Mason; A H Schene

2007-01-01

17

Long-term treatment of tardive dyskinesia with presynaptically acting dopamine-depleting agents.  

PubMed

Fourteen patients with TD, all but one also having tardive akathisia, were evaluated on presynaptically acting dopamine-depleting drugs, reserpine, TBZ, and AMT. Initially, the drugs were evaluated individually, but later AMT was used in combination with reserpine and with TBZ, since their different mechanisms of action allowed for increased potency when they were used in this combination. All but one patient responded to this therapeutic approach. Parkinsonism was easily induced, however. Most patients varied during the day between mild parkinsonism and mild dyskinesia-akathisia. It was difficult to have patients at the normal level between these two conditions. The addition of carbidopa/levodopa in one patient not only relieved the side effect of parkinsonism but may have also accelerated a remission from TD and akathisia. Although postural hypotension was a common adverse effect in patients receiving reserpine, especially in combination with AMT, it did not develop in patients taking TBZ, either alone or in combination with AMT. This observation suggests that TBZ may be less effective depleting monoamines in the periphery than in the central nervous system. Since reserpine is available commercially in the United States whereas TBZ is not, reserpine may be the drug of choice in treating patients with TD or tardive akathisia. The addition of AMT will increase the potency of this form of treatment. PMID:6858776

Fahn, S

1983-01-01

18

Sex-dependent changes in ADHD-like behaviors in juvenile rats following cortical dopamine depletion.  

PubMed

Reduced cortical dopamine levels have been observed in individuals with attention deficit hyperactivity disorder (ADHD). Global dopamine depletions by 6-hydroxydopamine (6-OHDA; with noradrenergic protection) in neonatal rats produces locomotor hyperactivity, with less known about how cortical depletion modulates risky behaviors. Here, we determined the effect of a medial prefrontal cortex (PFC) 6-OHDA depletions (30-60%) or sham microinjection at postnatal day 11 on behavior in male and female juvenile rats. Separate groups were studied for delay discounting (impulsive choice), novelty-preference, and preferences for cues and environments associated with cocaine (10, 20, and 40mg/kg), their extinction, and reinstatement with place conditioning. Because PFC D1 receptors play a role in these behaviors, confocal microscopy was used to measure D1-immunoreactive projections to the nucleus accumbens core. Both 6-OHDA males and females increased delay discounting relative to sham controls, although only 6-OHDA females increased novelty preferences. Preferences for cocaine-associated environments, their extinction, and reinstatement with a priming dose of cocaine were reduced in 6-OHDA subjects overall. However, impulsive choice at 5s positively correlated with preferences for cocaine-associated environments in 6-OHDA subjects, but not sham controls. As possible compensation for low dopamine levels, D1-immunoreactivity on traced neurons increased in 6-OHDA females; dopamine levels did not remain low in adolescent 6-OHDA males and D1 did not change. We believe that these modest depletions restricted to the PFC demonstrate the role of dopamine, and not norepinephrine, in understanding these behaviors in other animal models where cortical dopamine is reduced during development. PMID:24861711

Freund, Nadja; MacGillivilray, Heather T; Thompson, Britta S; Lukkes, Jodi L; Stanis, Jessica J; Brenhouse, Heather C; Andersen, Susan L

2014-08-15

19

Glutathione deficiency in Gclm null mice results in complex I inhibition and dopamine depletion following paraquat administration.  

PubMed

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

Liang, Li-Ping; Kavanagh, Terrance J; Patel, Manisha

2013-08-01

20

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

PubMed

We investigated the neuroprotective effect of the dopamine agonist, 3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine] against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP (30 mg/kg, i.p., twice, 16 h apart) causes significant dopamine depletion in nucleus caudatus putamen (NCP) by 1 week. 3-PPP had no effect on the monoamine oxidase-B activity (MAO-B) activity in NCP. 3-PPP did not affect dopamine uptake, whereas mazindol significantly blocked the uptake of dopamine dose dependently. MPTP-induced behavioral changes in mice were not reduced by pretreatment with 3-PPP. This dopamine agonist did not prevent dopamine depletion caused by MPTP. MPP+ (20 microM) significantly inhibited the cell proliferation of SH-SY5Y dopaminergic neuronal cells. 3-PPP had no effect on the SH-SY5Y neuronal cell growth in culture and did not block the MPP(+)-induced cytotoxicity. This study shows that the dopamine agonist 3-PPP failed to protect against MPTP-induced dopaminergic neurotoxicity. PMID:15002733

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

2004-02-01

21

Effect of dopamine-depleting brain lesions on suckling and weaning in rats  

Microsoft Academic Search

Rats given large dopamine (DA)-depleting brain lesions as adults exhibit severe impairments in ingestive behavior and sensorimotor function. In contrast to these well-known effects, the present 2 studies showed that virtually complete destruction of central dopaminergic neurons produced no such dysfunctions when it occurred in neonates (Sprague-Dawley). Ss continued to suckle and grow, albeit somewhat more slowly, and they could

John P. Bruno; Abigail M. Snyder; Edward M. Stricker

1984-01-01

22

Effects of asymmetric dopamine depletion on sensitivity to rewarding and aversive stimuli in Parkinson's disease.  

PubMed

The onset and progression of Parkinson's disease (PD) motor symptoms is generally asymmetric, reflecting differential extent of nigral pathology and resulting dopamine depletion in each of the hemispheres. Given the role of dopamine in processing rewarding and aversive events, and considering findings associating asymmetric neural activity with differential sensitivity to positive and negative stimuli, the current study examined the possibility that dopamine asymmetry in PD is related to differential approach and avoidance tendencies. An original task assessing and comparing sensitivity to positive and negative probabilistic feedback was administered to 29 right-handed participants with idiopathic PD, 16 with predominant right-side and 13 with predominant left-side motor symptoms, to compare the two groups. As dopamine replacement therapy (DRT) has shown different effects on reward and punishment processing, all participants were assessed in both off- and on-medication states. As predicted, when off medication, participants with relatively greater dopamine deficit in the left hemisphere minimized losses better than they increased gains, while those with a greater right hemisphere deficit showed a trend toward the opposite pattern. Medication reversed the relationship between gain and loss sensitivity in the left-hemisphere PD group, but not in the right-hemisphere group. Particularly in the left-hemisphere PD group, findings support the possibility that subcortical dopaminergic asymmetry is reflected in behaviorally-expressed approach and avoidance tendencies. Furthermore, the effects of DRT on approach and avoidance appear to interact with asymmetry, shedding light on previous conclusions regarding the role of dopamine in reinforcement processing. PMID:23422331

Maril, Sari; Hassin-Baer, Sharon; Cohen, Oren S; Tomer, Rachel

2013-04-01

23

Methamphetamine-induced rapid decrease in dopamine transporter function: role of dopamine and hyperthermia.  

PubMed

Single and multiple high-dose administrations of methamphetamine (METH) differentially decrease dopamine (DA) transporter (DAT) function, as assessed by measuring [(3)H]DA uptake into rat striatal synaptosomes prepared 1 h after treatment. Prevention of METH-induced hyperthermia attenuated the decrease in DAT activity induced by multiple injections of the stimulant. Likewise, this decrease was attenuated by previous depletion of striatal DA levels using alpha-methyl-p-tyrosine (alphaMT) or pretreatment with the D1 and D2 antagonists SCH-23390 and eticlopride, respectively. However, METH-induced hyperthermia was also blocked by alphaMT and eticlopride. Reinstatement of hyperthermia to alphaMT- or eticlopride-pretreated rats partially restored the METH-induced decrease in DAT activity. In contrast, neither prevention of METH-induced hyperthermia depletion of DA, nor DA antagonists altered the decrease in DAT function induced by a single administration of METH. Pretreatment with the antioxidant N-t-butyl-alpha-phenylnitrone prevented part of the decrease in DAT function associated with multiple, but not a single, METH injections. Although not tested directly, additional data presented here suggest that the reduction in DAT activity induced by a single METH administration constitutes a part of the total reduction observed immediately after multiple administrations. Taken together, the results indicate that DA, hyperthermia, and oxygen radicals contribute to a component of the rapid decrease in DAT function induced by multiple injections of METH but do not appear to be associated with the reduction induced by a single administration of the stimulant. PMID:11082443

Metzger, R R; Haughey, H M; Wilkins, D G; Gibb, J W; Hanson, G R; Fleckenstein, A E

2000-12-01

24

Dopamine depletion in neonatal rats: effects on behavior and striatal dopamine release assessed by intracerebral microdialysis during adulthood.  

PubMed

Rats depleted of dopamine (DA) by intraventricular 6-hydroxydopamine (6-OHDA) in infancy show behavioral impairments as adults, but their basic sensory-motor functions and feeding abilities are intact; at least relative to the pronounced deficits seen in rats given similar treatment in adulthood. Here we investigate whether presynaptic changes culminating in enhanced DA release are present in adult rats that received neonatal damage, and whether these are of a sufficient magnitude to contribute to the sparing of function. We used microdialysis in rats during the resting state, walking on a treadmill, and after a systemic injection of amphetamine. It was found that neonatal 6-OHDA produced a nearly complete (less than 1% of control) depletion of DA in postmortem tissue, but this was not accompanied by a comparable decline in the basal extracellular concentrations of DA, which were only reduced by 12-54% of control values. In contrast, the extracellular concentrations of DA metabolites were greatly reduced, reflecting the post-mortem tissue concentrations of DA. Nevertheless, neonatally depleted animals were markedly deficient in their ability to respond to an amphetamine challenge, both behaviorally and in their ability to further increase DA release. Thus, following neonatal DA depletion there appear to be extensive changes in the few remaining DA terminals that are sufficient to maintain relatively high extracellular (and presumably synaptic) concentrations of DA during the resting state, but the capacity of the remaining DA neurons to respond to increased demand is very limited. This presynaptic compensatory response may play a role in the sparing of behavioral function seen following neonatal damage. PMID:1692503

Castańeda, E; Whishaw, I Q; Lermer, L; Robinson, T E

1990-01-29

25

Dopamine (3-hydroxytyramine) replacement and metabolism in sympathetic nerve and adrenal medullary depletions after prolonged thermal injury  

PubMed Central

After severe thermal injury, the adrenal medulla and the sympathetic nerves can be partially or totally depleted of their adrenaline (epinephrine) and noradrenaline (norepinephrine). The purpose of this paper is to elucidate the rate at which dopamine-2-14C, a precursor of noradrenaline, is synthesized into noradrenaline and noradrenaline metabolic products, thereby giving some indication as to dopamine's utilization, turnover, and possible use in treating such noradrenaline-adrenaline depletions. Three burned subjects, 3 wk postburn, were infused with 104.6 ?c (872 ?g) of dopamine-2-14C for 4 hr. Urine was collected at various hourly intervals for the 1st day, and thereafter for 4 days, assayed, and compared with the metabolism of dopamine in normal subjects. Methods for separating, identifying, and counting radioactivity of the various metabolic products of dopamine are described. Normally 87.6 ±3.1% of the total radioactivity is recovered within 24 hr after an infusion of dopamine-2-14C, but in the three severely burned patients, this value was increased to 93.1, 97.3, and 97.5% in 24 hr. There was a marked decrease in the percentage of radioactivity recovered as noradrenaline in all collection periods, and in contrast to normal subjects, no radioactive noradrenaline was recovered after 24 hr. Concomitantly, there was an increase in radioactivity recovered as metabolic products of noradrenaline, reflecting a compensatory shift toward noradrenaline synthesis and utilization at the expense of the dopamine metabolic products. The results indicate that in the burned patients the infused dopamine-2-14C was rapidly synthesized into noradrenaline and then rapidly released and metabolized. From these results it seems evident that dopamine would be a useful adjunct in the treatment of sympathico-adrenal medullary depletion in burns. Images

Goodall, McC.; Alton, Harold

1969-01-01

26

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

PubMed Central

Introduction The neurotransmitter dopamine has frequently been implicated in reward processing but is also, increasingly, implicated in punishment processing. We have previously shown that both patients with Parkinson's disease and healthy individuals with low dopamine (DA) synthesis are better at reversal learning based on punishment than reward. Here, we extend these prior findings by examining the effects of artificially reducing DA synthesis in healthy individuals performing this previously employed task. Methods In a double-blind, placebo-controlled crossover design, we applied the acute tyrosine and phenylalanine depletion (ATPD) procedure to reduce global DA synthesis in 15 female and 14 male subjects. Each subject performed the reward- and punishment-based reversal-learning paradigm. Results There was a significant three-way interaction between ATPD, the valence of the outcome signalling reversal and the gender of the participants. Examination of punishment and reward-based reversals separately revealed that this was driven by a significant improvement in punishment processing in female but not male subjects following DA depletion. Conclusions Reducing DA synthesis in healthy individuals shifted sensitivity of performance from reward to punishment processing. Gender differences in DA synthesis might underlie the selectivity of this effect to female subjects. Such gender biases may go some way towards explaining the gender biases in certain psychiatric disorders such as depression and Parkinson's disease.

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

2010-01-01

27

Effect of dopamine-depleting brain lesions on suckling and weaning in rats.  

PubMed

Rats given large dopamine-depleting brain lesions as adults exhibit severe impairments in ingestive behavior and sensorimotor function. In contrast to these well-known effects, virtually complete destruction of central dopaminergic neurons produced no such dysfunctions when it occurred in neonates. Indeed, rats continued to suckle and grow, albeit somewhat more slowly, and they could be weaned readily when they were 27 days old. Although most brain-damaged animals did not survive weaning when they were 18 days old, whereas controls exhibited no difficulty, this failure appears to be the consequence of their reduced body weight and related inability to maintain body temperature in a relatively cool environment (22 degrees C). Such premature weaning occurred more successfully when growth was stimulated by rearing brain-damaged pups in small litters or when ambient temperatures were raised to 31 degrees C so as to minimize heat loss. These results demonstrate that the effects of near-total dopamine-depleting brain lesions are considerably less severe when they occur in infants than when they occur in adults, and, consequently, they reveal a capacity for neural plasticity during development that is no longer present at maturity. PMID:6696795

Bruno, J P; Snyder, A M; Stricker, E M

1984-02-01

28

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.

2013-01-01

29

[Pathological gambling induced by dopamine agonists].  

PubMed

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

2011-08-01

30

Mitochondrial stress-induced dopamine efflux and neuronal damage by malonate involves the dopamine transporter.  

PubMed

Endogenous striatal dopamine (DA) overflow has been associated with neuropathological conditions resulting from ischemia, psychostimulants, and metabolic inhibition. Malonate, a reversible inhibitor of succinate dehydrogenase, models the effects of energy impairment in neurodegenerative disorders. We have previously reported that the striatal DA efflux and damage to DA nerve terminals resulting from intrastriatal malonate infusions is prevented by prior DA depletion, suggesting that DA plays a role in the neuronal damage. We presently report that the malonate-induced DA efflux is partially mediated by reverse transport of DA from the cytosol to the extracellular space via the DA transporter (DAT). Pharmacological blockade of the DAT with a series of structurally different inhibitors [cocaine, mazindol, 1-(2-(bis(4-fluophenyl methoxy) ethyl)-4-(3-(4-fluorophenyl)-propyl)piperazine) dimethane sulfonate (GBR 13098) and methyl(-)-3beta-(p-fluorophenyl)-1alphaH,5alphaH-tropane-2beta-carboxylate1,5-naphthalene (Win 35,428)] attenuated malonate-induced DA overflow in vivo and protected mice against subsequent damage to DA nerve terminals. Consistent with these findings, the DAT inhibitors prevented malonate-induced damage to DA neurons in mesencephalic cultures and also protected against the loss of GABA neurons in this system. The DAT inhibitors did not modify malonate-induced formation of reactive oxygen species or lactate production, indicating that the DAT inhibitors neither exert antioxidant effects nor interfere with the actions of malonate. Taken together, these findings provide direct evidence that mitochondrial impairment and metabolic stress cause striatal DA efflux via the DAT and suggest that disruptions in DA homeostasis resulting from energy impairment may contribute to the pathogenesis of neurodegenerative diseases. PMID:17090704

Moy, Lily Y; Wang, Sheng-Ping; Sonsalla, Patricia K

2007-02-01

31

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.

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

2014-01-01

32

Neuroprotection by pramipexole against dopamine- and levodopa-induced cytotoxicity  

Microsoft Academic Search

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

Linglong Zou; Joseph Jankovic; Dominic B. Rowe; Wenjie Xie; Stanley H. Appel; Weidong Le

1999-01-01

33

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

PubMed Central

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

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

2007-01-01

34

The role of forebrain dopamine systems in amphetamine induced stereotyped behavior in the rat  

Microsoft Academic Search

The caudate nucleus or the tuberculum olfactorium of the rat was lesioned by bilateral stereotaxic injection of 6-hydroxydopamine. The degree of dopamine depletion was assessed by a sensitive regional dopamine assay and revealed severe depletions in the lesioned areas. The locomotor response to a low dose of d-amphetamine was not modified by either lesion. However, the stereotypy response to a

Ian Creese; Susan D. Iversen

1974-01-01

35

Dopamine-Induced Conformational Changes in Alpha-Synuclein  

PubMed Central

Background Oligomerization and aggregation of ?-synuclein molecules play a major role in neuronal dysfunction and loss in Parkinson's disease [1]. However, ?-synuclein oligomerization and aggregation have mostly been detected indirectly in cells using detergent extraction methods [2], [3], [4]. A number of in vitro studies showed that dopamine can modulate the aggregation of ?-synuclein by inhibiting the formation of or by disaggregating amyloid fibrils [5], [6], [7]. Methodology/Principal Findings Here, we show that ?-synuclein adopts a variety of conformations in primary neuronal cultures using fluorescence lifetime imaging microscopy (FLIM). Importantly, we found that dopamine, but not dopamine agonists, induced conformational changes in ?-synuclein which could be prevented by blocking dopamine transport into the cell. Dopamine also induced conformational changes in ?-synuclein expressed in neuronal cell lines, and these changes were also associated with alterations in oligomeric/aggregated species. Conclusion/Significance Our results show, for the first time, a direct effect of dopamine on the conformation of ?-synuclein in neurons, which may help explain the increased vulnerability of dopaminergic neurons in Parkinson's disease.

Outeiro, Tiago F.; Klucken, Jochen; Bercury, Kathryn; Tetzlaff, Julie; Putcha, Preeti; Oliveira, Luis M. A.; Quintas, Alexandre; McLean, Pamela J.; Hyman, Bradley T.

2009-01-01

36

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

PubMed Central

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

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

2013-01-01

37

D-amphetamine-induced release of "newly synthesized" and "stored" dopamine from the caudate nucleus in vivo.  

PubMed

The lateral and third ventricles of anesthetized cats were perfused continuously with artificial cerebrospinal fluid (CSF) containing 3H-tyrosine and the perfusate was analyzed for 3H-catecholamines. The addition of d-amphetamine sulfate to the perfusing CSF for 2 hours, beginning 2 hours after the start of the 3H-tyrosine perfusion, caused an immediate increase in the efflux of 3H-dopamine. The efflux of this amine declined subsequently despite the continued presence of amphetamine in the CSF. The addition of alpha-methyltyrosine to the CSF concurrently with the d-amphetamine did not markedly alter the immediate increase but accelerated the subsequent decline in the efflux of 3H-dopamine. This suggests that ampetamine initially releases dopamine from a "strong pool," but continuous release is dependent upon ongoing amine synthesis. The addition of d-amphetamine to the 3H-tyrosine containing CSF at the start of perfusion immediately increased the efflux of 3H-dopamine. This response was completely blocked by the presence of alpha-methyltyrosine in the CSF. Pretreatment of cats with reserpine effectively depleted the caudate nucleus of endogenous and 3H-dopamine, but did not alter the ability of d-amphetamine to increase the efflux of 3H-dopamine. Indeed, the amount of 3H-dopamine released during each collection period by either intraventricular or intravenous administration of d-amphetamine was higher than the content of the labeled amine remaining in the whole caudate nucleus. These results suggest that damphetamine can release both "stored" and "newly synthesized" 3H-dopamine from the caudate nucleus, but that the maintenance of the amphetamine-induced release of dopamine is dependent upon the newly synthetized pool. PMID:1120962

Chiueh, C C; Moore, K E

1975-03-01

38

Dopamine precursor depletion impairs structure and efficiency of resting state brain functional networks.  

PubMed

Spatial patterns of functional connectivity derived from resting brain activity may be used to elucidate the topological properties of brain networks. Such networks are amenable to study using graph theory, which shows that they possess small world properties and can be used to differentiate healthy subjects and patient populations. Of particular interest is the possibility that some of these differences are related to alterations in the dopamine system. To investigate the role of dopamine in the topological organization of brain networks at rest, we tested the effects of reducing dopamine synthesis in 13 healthy subjects undergoing functional magnetic resonance imaging. All subjects were scanned twice, in a resting state, following ingestion of one of two amino acid drinks in a randomized, double-blind manner. One drink was a nutritionally balanced amino acid mixture, and the other was tyrosine and phenylalanine deficient. Functional connectivity between 90 cortical and subcortical regions was estimated for each individual subject under each dopaminergic condition. The lowered dopamine state caused the following network changes: reduced global and local efficiency of the whole brain network, reduced regional efficiency in limbic areas, reduced modularity of brain networks, and greater connection between the normally anti-correlated task-positive and default-mode networks. We conclude that dopamine plays a role in maintaining the efficient small-world properties and high modularity of functional brain networks, and in segregating the task-positive and default-mode networks. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'. PMID:24412649

Carbonell, Felix; Nagano-Saito, Atsuko; Leyton, Marco; Cisek, Paul; Benkelfat, Chawki; He, Yong; Dagher, Alain

2014-09-01

39

Expression and activity of nitric oxide synthase isoforms in methamphetamine-induced striatal dopamine toxicity.  

PubMed

Nitric oxide is implicated in methamphetamine (METH)-induced neurotoxicity; however, the source of the nitric oxide has not been identified. Previous work has also revealed that animals with partial dopamine loss induced by a neurotoxic regimen of methamphetamine fail to exhibit further decreases in striatal dopamine when re-exposed to methamphetamine 7-30 days later. The current study examined nitric oxide synthase expression and activity and protein nitration in striata of animals administered saline or neurotoxic regimens of methamphetamine at postnatal days 60 and/or 90, resulting in four treatment groups: Saline:Saline, METH:Saline, Saline:METH, and METH:METH. Acute administration of methamphetamine on postnatal day 90 (Saline:METH and METH:METH) increased nitric oxide production, as evidenced by increased protein nitration. Methamphetamine did not, however, change the expression of endothelial or inducible isoforms of nitric oxide synthase, nor did it change the number of cells positive for neuronal nitric oxide synthase mRNA expression or the amount of neuronal nitric oxide synthase mRNA per cell. However, nitric oxide synthase activity in striatal interneurons was increased in the Saline:METH and METH:METH animals. These data suggest that increased nitric oxide production after a neurotoxic regimen of methamphetamine results from increased nitric oxide synthase activity, rather than an induction of mRNA, and that constitutively expressed neuronal nitric oxide synthase is the most likely source of nitric oxide after methamphetamine administration. Of interest, animals rendered resistant to further methamphetamine-induced dopamine depletions still show equivalent degrees of methamphetamine-induced nitric oxide production, suggesting that nitric oxide production alone in response to methamphetamine is not sufficient to induce acute neurotoxic injury. PMID:23230214

Friend, Danielle M; Son, Jong H; Keefe, Kristen A; Fricks-Gleason, Ashley N

2013-02-01

40

The Subthalamic Nucleus becomes a Generator of Bursts in the Dopamine-Depleted State. Its High Frequency Stimulation Dramatically Weakens Transmission to the Globus Pallidus  

PubMed Central

Excessive burst firing in the dopamine-depleted basal ganglia correlates with severe motor symptoms of Parkinson's disease that are attenuated by high frequency electrical stimulation of the subthalamic nucleus (STN). Here we test the hypothesis that pathological bursts in dopamine-deprived basal ganglia are generated within the STN and transmitted to globus pallidus neurons. To answer this question we recorded excitatory synaptic currents and potentials from subthalamic and pallidal neurons in the basal ganglia slice (BGS) from dopamine-depleted mice while continuously blocking GABAA receptors. In control mice, a single electrical stimulus delivered to the internal capsule or the rostral pole of the STN evoked a short duration, small amplitude, monosynaptic EPSC in subthalamic neurons. In contrast, in the dopamine-depleted BGS, this monosynaptic EPSC was amplified and followed by a burst of polysynaptic EPSCs that eventually reverberated three to seven times, providing a long lasting response that gave rise to bursts of EPSCs and spikes in GP neurons. Repetitive (10–120 Hz) stimulation delivered to the STN in the dopamine-depleted BGS attenuated STN-evoked bursts of EPSCs in pallidal neurons after several minutes of stimulation but only high frequency (90–120 Hz) stimulation replaced them with small amplitude EPSCs at 20 Hz. We propose that the polysynaptic pathway within the STN amplifies subthalamic responses to incoming excitation in the dopamine-depleted basal ganglia, thereby transforming the STN into a burst generator and entraining pallidal neurons in pathogenic bursting activities. High frequency stimulation of the STN prevents the transmission of this pathological activity to globus pallidus and imposes a new glutamatergic synaptic noise on pallidal neurons.

Ammari, Rachida; Bioulac, Bernard; Garcia, Liliana; Hammond, Constance

2011-01-01

41

METHAMPHETAMINE-INDUCED DOPAMINE TERMINAL DEFICITS IN THE NUCLEUS ACCUMBENS ARE EXACERBATED BY REWARD-ASSOCIATED CUES AND ATTENUATED BY CB1 RECEPTOR ANTAGONISM  

PubMed Central

Methamphetamine (METH) exposure is primarily associated with deleterious effects to dopaminergic neurons. While several studies have implicated the endocannabinoid system in METH’s locomotor, rewarding and neurochemical effects, a role for this signaling system in METH’s effects on dopamine terminal dynamics has not been elucidated. Given that CB1 receptor blockade reduces the acute potentiation of phasic extracellular dopamine release from other psychomotor stimulant drugs and that the degree of acute METH-induced increases in extracellular dopamine levels is related to the severity of dopamine depletion, we predicted that pretreatment with the CB1 receptor antagonist rimonabant would reduce METH-induced alterations at dopamine terminals. Furthermore, we hypothesized that administration of METH in environments where reward associated-cues were present would potentiate METH’s acute effects on dopamine release in the nucleus accumbens and exacerbate changes in dopamine terminal activity. Fast-scan cyclic voltammetry was used to measure electrically-evoked dopamine release in the nucleus accumbens and revealed markers of compromised dopamine terminal integrity nine days after a single dose of METH. These were exacerbated in animals that received METH in the presence of reward-associated cues, and attenuated in rimonabant-pretreated animals. While these deficits in dopamine dynamics were associated with reduced operant responding on days following METH administration in animals treated with only METH, rimonabant-pretreated animals exhibited levels of operant responding comparable to control. Moreover, dopamine release correlated significantly with changes in lever pressing behavior that occurred on days following METH administration. Together these data suggest that the endocannabinoid system is involved in the subsecond dopaminergic response to METH.

Loewinger, Gabriel C.; Beckert, Michael V.; Tejeda, Hugo A.; Cheer, Joseph F.

2012-01-01

42

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

PubMed

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

1999-01-01

43

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

Microsoft Academic Search

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

Lakshmi N. P. Voruganti; A. George Awad

2006-01-01

44

Cyclooxygenase-independent neuroprotective effects of aspirin against dopamine quinone-induced neurotoxicity.  

PubMed

Prostaglandin H synthase exerts not only cyclooxygenase activity but also peroxidase activity. The latter activity of the enzyme is thought to couple with oxidation of dopamine to dopamine quinone. Therefore, it has been proposed that cyclooxygenase inhibitors could suppress dopamine quinone formation. In the present study, we examined effects of various cyclooxygenase inhibitors against excess methyl L-3,4-dihydroxyphenylalanine (L-DOPA)-induced quinoprotein (protein-bound quinone) formation and neurotoxicity using dopaminergic CATH.a cells. The treatment with aspirin inhibited excess methyl L-DOPA-induced quinoprotein formation and cell death. However, acetaminophen did not show protective effects, and indomethacin and meloxicam rather aggravated these methyl L-DOPA-induced changes. Aspirin and indomethacin did not affect the level of glutathione that exerts quenching dopamine quinone in dopaminergic cells. In contrast with inhibiting effects of higher dose in the previous reports, relatively lower dose of aspirin that affected methyl L-DOPA-induced quinoprotein formation and cell death failed to prevent cyclooxygenase-induced dopamine chrome generation in cell-free system. Furthermore, aspirin but not acetaminophen or meloxicam showed direct dopamine quinone-scavenging effects in dopamine-semiquinone generating systems. The present results suggest that cyclooxygenase shows little contribution to dopamine oxidation in dopaminergic cells and that protective effects of aspirin against methyl L-DOPA-induced dopamine quinone neurotoxicity are based on its cyclooxygenase-independent property. PMID:22674083

Asanuma, Masato; Miyazaki, Ikuko; Kikkawa, Yuri; Kimoto, Naotaka; Takeshima, Mika; Murakami, Shinki; Miyoshi, Ko

2012-09-01

45

Dopamine Induces Ca2+ Signaling in Astrocytes through Reactive Oxygen Species Generated by Monoamine Oxidase  

PubMed Central

Dopamine is a neurotransmitter that plays a major role in a variety of brain functions, as well as in disorders such as Parkinson disease and schizophrenia. In cultured astrocytes, we have found that dopamine induces sporadic cytoplasmic calcium ([Ca2+]c) signals. Importantly, we show that the dopamine-induced calcium signaling is receptor-independent in midbrain, cortical, and hippocampal astrocytes. We demonstrate that the calcium signal is initiated by the metabolism of dopamine by monoamine oxidase, which produces reactive oxygen species and induces lipid peroxidation. This stimulates the activation of phospholipase C and subsequent release of calcium from the endoplasmic reticulum via the inositol 1,4,5-trisphosphate receptor mechanism. These findings have major implications on the function of astrocytes that are exposed to dopamine and may contribute to understanding the physiological role of dopamine.

Vaarmann, Annika; Gandhi, Sonia; Abramov, Andrey Y.

2010-01-01

46

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.

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

2014-01-01

47

Methamphetamine-induced striatal dopamine release, behavior changes and neurotoxicity in BALB/c mice.  

PubMed

The behaviors associated with the neurotoxic effects of methamphetamine were evaluated in BALB/c mice. Hyperthermia and behavioral observations were measured 60 min after each subcutaneous injection of methamphetamine (4x4 or 8 mg/kg) or saline, each given 2 h apart. The behavioral observations included stereotyped behaviors, incidence of hemorrhage in breast, salivation and self-injurious behavior (SIB). Repeated administration of methamphetamine produced these behavioral changes and hyperthermia, but resulted in hypothermia by the final injection (8 mg/kg). In addition, the methamphetamine treatment induced a long-lasting dopamine depletion of similar magnitude in the 4 and 8 mg/kg-treated animals. In a time course study striatal monoamine levels were measured 60 min after each injection of these doses. The first and second injections of methamphetamine (8 mg/kg) produced a drastic increase in striatal 3-methoxytyramine; this failed to occur after the third or fourth injection of the same dose. In contrast, 4 mg/kg of methamphetamine also produced an increase in 3-methoxytyramine after the second and third injections of the drug and, in this case, these were maintained for the duration of the treatment. Striatal 3, 4-dihydroxyphenylacetic acid levels also drastically decreased following both doses of methamphetamine, suggesting inhibition of monoamine oxidase in striatum. Moreover, a single injection of methamphetamine increased striatal 2,3-dihydroxybenzoic acid formation. These results suggest that the incidence of hyperthermia, SIB and striatal dopamine neurotoxicity are closely linked to striatal dopamine release and inhibition of monoamine oxidase produced by methamphetamine in BALB/c mice. PMID:10884597

Kita, T; Matsunari, Y; Saraya, T; Shimada, K; O'Hara, K; Kubo, K; Wagner, G C; Nakashima, T

2000-10-01

48

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

1973-01-01

49

Dopamine uptake blockers nullify methamphetamine-induced decrease in dopamine uptake and plasma membrane potential in rat striatal synaptosomes.  

PubMed

Rat striatal synaptosomes showed a reduced capacity to generate a membrane potential after being exposed to methamphetamine (METH) for 1 h. As a consequence, the dopamine (DA) synaptosomes were impeded in their electrogenic-dependent reuptake of dopamine. The capacity for METH-exposed nerve terminals to generate a membrane potential may contribute to the ability of METH to destroy dopaminergic neurons. DA uptake inhibitors (DAUIs) were found to counteract the METH-induced decrease in synaptosomal [3H]DA Vmax by stablizing METH-induced reductions in PMP. Because DAUIs showed the same effects as a Na+-channel blocker, DAUIs may prevent METH-induced destruction of dopaminergic neurons by raising plasma membrane potential. PMID:11085320

Westphalen, R I; Stadlin, A

2000-09-01

50

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

1997-05-01

51

Loss of asymmetric spine synapses in prefrontal cortex of motor-asymptomatic, dopamine-depleted, cognitively impaired MPTP-treated monkeys  

PubMed Central

Parkinson's disease is usually characterized as a movement disorder; however cognitive abilities that are dependent on the prefrontal cortex decline at an early stage of the disease in most patients. The changes that underlie cognitive deficits in Parkinson’s disease are not well understood. We hypothesize that reduced dopamine signaling in the prefrontal cortex in Parkinson’s disease is a harbinger of detrimental synaptic changes in pyramidal neurons in the prefrontal cortex whose function is necessary for normal cognition. Our previous data showed that monkeys exposed to the neurotoxin, MPTP, but not exhibiting overt motor deficits (motor-asymptomatic), displayed cognitive deficits in prefrontal cortex-dependent tasks. The present results demonstrate that motor-asymptomatic MPTP-treated monkeys have a reduced dopamine concentration and a substantially lower number (50%) of asymmetric (excitatory) spine synapses in layer II/III, but not layer V, of the dorsolateral prefrontal cortex, compared with controls. In contrast, neither dopamine concentration nor asymmetric synapse number was altered in the entorhinal cortex of MPTP-treated monkeys. Together these findings suggest that the number of asymmetric spine synapses on dendrites in the prefrontal cortex is dopamine-dependent and that the loss of synapses may be a morphological substrate of the cognitive deficits induced by a reduction in dopamine neurotransmission in this region. Modulation of asymmetric spine synapse number in prefrontal cortex represents a novel neuroplastic function for dopamine.

Elsworth, John D.; Leranth, Csaba; Redmond, D.Eugene; Roth, Robert H.

2013-01-01

52

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

PubMed

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

2014-08-01

53

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

1995-05-01

54

Mesencephalic neural stem (progenitor) cells develop to dopaminergic neurons more strongly in dopamine-depleted striatum than in intact striatum.  

PubMed

Epidermal growth factor (EGF)/fibroblast growth factor (FGF)-responsive stem (progenitor) cells from embryonic brain have self-renewing and multipotent properties and thus are good candidates for donor cells in neural transplantation. However, the survival and differentiation to mature neurons after grafting of stem cells into adult brain are rather poor. We hypothesize that the differentiation of stem cells to mature neurons, such as dopaminergic (DAergic) neurons, is dependent on environmental cues that control the ontogenic development. We compared the survival and differentiation between mesencephalic (MS) and cortical (CTx) stem (progenitor) cells, following grafting into bilateral striata of hemiparkinsonian model rats. MS and CTx stem cells were prepared from E12 rats and proliferated in serum-free medium with EGF or basic FGF for 2 weeks. One day after being primed to differentiate, the cell suspensions of both origins were grafted into the bilateral striata of adult rats that had unilateral 6-OHDA lesions in the substantia nigra. MS cells differentiated to tyrosine hydroxylase (TH)-positive neurons more strongly in DA-depleted striatum than in intact striatum, and methamphetamine-induced rotation was ameliorated in half of the grafted animals. Rosette-like cell aggregation and dysfunction of the blood-brain barrier (BBB) were less in and around the grafts in DA-depleted striatum, suggesting less proliferation and more differentiation of MS stem cells in DA-depleted striatum. Neither TH-positive neurons nor behavioral amelioration were detected following CTx stem (progenitor) cell transplantation in the striata. Data suggest that the DA-depleted striatum offers a suitable environment for MS stem (progenitor) cells to differentiate into mature DAergic neurons. PMID:10877931

Nishino, H; Hida, H; Takei, N; Kumazaki, M; Nakajima, K; Baba, H

2000-07-01

55

Depletion-induced structure and dynamics in bimodal colloidal suspensions.  

SciTech Connect

Combined small angle x-ray scattering and x-ray photon correlation spectroscopy studies of moderately concentrated bimodal hard-sphere colloidal suspensions in the fluid phase show that depletion-induced demixing introduces spatially heterogeneous dynamics with two distinct time scales. The adhesive nature, as well as the mobility, of the large particles is determined by the level of interaction within the monomodal domains. This interaction is driven by osmotic forces, which are governed by the relative concentration of the constituents.

Sikorski, M.; Sandy, A. R.; Narayanan, S. (X-Ray Science Division)

2011-05-03

56

Dopamine induces proteasome inhibition in neural PC12 cell line  

Microsoft Academic Search

The autoxidation and enzymatic catabolism of dopamine results in the generation of reactive oxygen species (ROS), which may possibly contribute to oxidative stress in multiple neurodegenerative disorders. Recent studies indicate that proteasome inhibition occurs in numerous neurodegenerative conditions, possibly as the result of oxidative stress, although the effects of dopamine on proteasome activity have not been determined. In the present

Jeffrey N Keller; Feng F Huang; Edgardo R Dimayuga; William F Maragos

2000-01-01

57

Renal hemodynamics in radiocontrast medium-induced renal dysfunction: A role for dopamine-1 receptors  

Microsoft Academic Search

Renal hemodynamics in radiocontrast medium-induced renal dysfunction: A role for dopamine-1 receptors.BackgroundRadiocontrast medium (RCM) administration induces a transient increase in renal blood flow (RBF), followed by a prolonged vasoconstriction. This vasoconstrictor phase in RBF is accompanied by a decrement in glomerular filtration rate (GFR). Nonselective dopamine (DA) receptor stimulation is known to increase RBF and GFR. Clinical studies, however, fail

George L. Bakris; Nancy A. Lass; Dana Glock

1999-01-01

58

Mechanisms Underlying Methamphetamine-Induced Dopamine Transporter Complex Formation  

PubMed Central

Repeated, high-dose methamphetamine (METH) administrations cause persistent dopaminergic deficits in rodents, nonhuman primates, and humans. In rats, this treatment also causes the formation of high-molecular mass (greater than approximately 120 kDa) dopamine transporter (DAT)-associated complexes, the loss of DAT monomer immunoreactivity, and a decrease in DAT function, as assessed in striatal synaptosomes prepared 24 h after METH treatment. The present study extends these findings by demonstrating the regional selectivity of DAT complex formation and monomer loss because these changes in DAT immunoreactivity were not observed in the nucleus accumbens. Furthermore, DAT complex formation was not a consequence limited to METH treatment because it was also caused by intrastriatal administration of 6-hydroxydopamine. Pretreatment with the D2 receptor antagonist, eticlopride [S-(-)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride], but not the D1 receptor antagonist, SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride], attenuated METH-induced DAT complex formation. Eticlopride pretreatment also attenuated METH-induced DAT monomer loss and decreases in DAT function; however, the attenuation was much less pronounced than the effect on DAT complex formation. Finally, results also revealed a negative correlation between METH-induced DAT complex formation and DAT activity. Taken together, these data further elucidate the underlying mechanisms and the functional consequences of repeated administrations of METH on the DAT protein. Furthermore, these data suggest a multifaceted role for D2 receptors in mediating METH-induced alterations of the DAT and its function.

Hadlock, Gregory C.; Baucum, Anthony J.; King, Jill L.; Horner, Kristen A.; Cook, Glen A.; Gibb, James W.; Wilkins, Diana G.; Hanson, Glen R.; Fleckenstein, Annette E.

2009-01-01

59

Mechanisms underlying methamphetamine-induced dopamine transporter complex formation.  

PubMed

Repeated, high-dose methamphetamine (METH) administrations cause persistent dopaminergic deficits in rodents, nonhuman primates, and humans. In rats, this treatment also causes the formation of high-molecular mass (greater than approximately 120 kDa) dopamine transporter (DAT)-associated complexes, the loss of DAT monomer immunoreactivity, and a decrease in DAT function, as assessed in striatal synaptosomes prepared 24 h after METH treatment. The present study extends these findings by demonstrating the regional selectivity of DAT complex formation and monomer loss because these changes in DAT immunoreactivity were not observed in the nucleus accumbens. Furthermore, DAT complex formation was not a consequence limited to METH treatment because it was also caused by intrastriatal administration of 6-hydroxydopamine. Pretreatment with the D2 receptor antagonist, eticlopride [S-(-)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride], but not the D1 receptor antagonist, SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride], attenuated METH-induced DAT complex formation. Eticlopride pretreatment also attenuated METH-induced DAT monomer loss and decreases in DAT function; however, the attenuation was much less pronounced than the effect on DAT complex formation. Finally, results also revealed a negative correlation between METH-induced DAT complex formation and DAT activity. Taken together, these data further elucidate the underlying mechanisms and the functional consequences of repeated administrations of METH on the DAT protein. Furthermore, these data suggest a multifaceted role for D2 receptors in mediating METH-induced alterations of the DAT and its function. PMID:19141713

Hadlock, Gregory C; Baucum, Anthony J; King, Jill L; Horner, Kristen A; Cook, Glen A; Gibb, James W; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

2009-04-01

60

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.

Kachadourian, Remy; Day, Brian J.

2014-01-01

61

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

PubMed

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

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

2014-06-01

62

Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition.  

PubMed

The authors developed a novel positron emission tomography method to estimate changes in the synaptic level of dopamine ([DA]) induced by direct dopamine agonists (for example, apomorphine) in patients with Parkinson disease. The method is based on the typical asymmetry of the nigrostriatal lesion that often occurs in Parkinson disease. Using the between-side difference (ipsilateral (I) and contralateral (C) putamen to the more affected body side) of the inverse of the putamen [11C]raclopride binding potential (BP), the authors obtained [equation: see text] at baseline (that is, before apomorphine administration) and [equation: see text] after apomorphine administration (assuming the concentration of apomorphine is equal in both putamina). The between-side difference in the estimated synaptic concentration of dopamine (diff[DA]) should remain constant unless apomorphine affects dopamine release differently between the two sides. The authors found that apomorphine given subcutaneously at doses of 0.03 and 0.06 mg/kg induced significant changes in their estimate of diff[DA] (P < 0.05). Such changes were more pronounced when only patients with a stable response to levodopa were considered (P < 0.01). These findings provide in vivo evidence that direct dopamine agonists can inhibit the release of endogenous dopamine. The authors propose that this effect is mainly mediated by the activation of presynaptic D2/D3 dopamine receptors. PMID:11598492

de La Fuente-Fernández, R; Lim, A S; Sossi, V; Holden, J E; Calne, D B; Ruth, T J; Stoessl, A J

2001-10-01

63

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

PubMed

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

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

2000-12-15

64

Tyramine-induced vasodilation mediated by dopamine contamination: a paradox resolved.  

PubMed

We reported previously that intravenous administration of tyramine induced a paradoxical forearm vasodilation and an increase in plasma dopamine, raising the possibility that dopamine is released by or converted from tyramine in vivo. Alternatively, tyramine can be nonenzymatically oxidized into dopamine in vitro, and this contamination may be responsible for the increase in plasma dopamine and forearm vasodilation. To distinguish between these possibilities, we measured the hemodynamic and neurohumoral effects of an intravenous infusion of a specially prepared dopamine-free tyramine solution in 8 normal volunteers at a dose that increased systolic blood pressure by approximately 25 mm Hg (from 107+/-5 to 133+/-5 mm Hg; P <0.001) and compared it with an equivalent dose of norepinephrine. Tyramine increased plasma norepinephrine (139+/-18 to 226+/-30 pg/mL; P <0.02), its intraneuronal metabolite dihydroxyphenylglycol (980+/-73 to 2245+/-206 pg/mL; P <0.001), and systemic vascular resistance, but not plasma dopamine or its intraneuronal metabolite dihydroxyphenylacetic acid. Tyramine and norepinephrine produced nonsignificant increases in forearm vascular resistance. We conclude that tyramine-induced forearm vasodilation reported in previous studies is explained by the presence of dopamine contamination in tyramine preparations. Intravenous administration of dopamine-free tyramine and norepinephrine produced equivalent systemic vasoconstriction. The forearm vasculature was not useful in monitoring the vasoconstrictive effects of either agent. The possibility of dopamine contamination needs to be considered when interpreting previously published studies using tyramine as a pharmacological tool to assess sympathetic function, and it must be avoided in future studies. PMID:15967868

Jacob, Giris; Gamboa, Alfredo; Diedrich, André; Shibao, Cyndya; Robertson, David; Biaggioni, Italo

2005-08-01

65

Functional and Molecular Differentiation of the Dopamine System Induced by Neonatal Denervation  

Microsoft Academic Search

JOYCE, J. N., P. A. FROHNA AND B. S. NEAL-BELIVEAU. Functional and molecular differentiation of the dopamine system induced by neonatal denervation. NEUROSCI BIOBEHAV REV 20(3)453–486, 1996.—The administration of the neurotoxin 6-hydroxydopamine (6-OHDA) to damage the mesostriatal dopamine (DA) system in the neonate results in different neurochemical and behavioral consequences as compared to lesions made in adulthood. There have been

JEFFREY N. JOYCE; PAUL A. FROHNA; BETHANY S. NEAL-BELIVEAU

1996-01-01

66

Dopamine induces the expression of heme oxygenase-1 by human endothelial cells in vitro  

Microsoft Academic Search

Dopamine induces the expression of heme oxygenase-1 by human endothelial cells in vitro.BackgroundIn a retrospective study of the kidney transplantations performed at our institution, we found that the administration of dopamine (DA) to the organ donors resulted in a significant improvement of long-term organ survival of the retrieved kidneys. To study the mechanisms underlying the organ protection associated with the

Stefan P Berger; Mathias Hünger; Benito A Yard; Peter Schnuelle; Fokko J Van Der Woude

2000-01-01

67

Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens.  

PubMed

Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens (NAc). In the past, different techniques have targeted dopamine levels in the NAc to establish a basal concentration. In this study, we used in vivo fast scan cyclic voltammetry (FSCV) in the NAc of awake, freely moving rats. The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is, the measurement of dopamine 'transients'. These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc. A series of experiments were designed to probe regulation of extracellular dopamine. Lidocaine was infused into the ventral tegmental area, the site of dopamine cell bodies, to arrest neuronal firing. While there was virtually no instantaneous change in dopamine concentration, longer sampling revealed a decrease in dopamine transients and a time-averaged decrease in the extracellular level. Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc. To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter (VMAT2) inhibitor, tetrabenazine, to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals. Tetrabenazine almost abolished phasic dopamine release but increased extracellular dopamine to ?500?nM, presumably by inducing reverse transport by dopamine transporter (DAT). Taken together, data presented here show that average extracellular dopamine in the NAc is low (20-30?nM) and largely arises from phasic dopamine transients. PMID:22296263

Owesson-White, Catarina A; Roitman, Mitchell F; Sombers, Leslie A; Belle, Anna M; Keithley, Richard B; Peele, Jessica L; Carelli, Regina M; Wightman, R Mark

2012-04-01

68

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

PubMed Central

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

Rodrigues, P dos S; Dowling, J E

1990-01-01

69

Neutrophil depletion inhibits airway hyperresponsiveness induced by ozone exposure  

SciTech Connect

We studied whether ozone-induced hyperresponsiveness could be inhibited by neutrophil depletion in dogs. Responsiveness was assessed with dose-response curves of acetylcholine aerosol versus pulmonary resistance; depletion was assessed by counting neutrophils in venous blood and in biopsies of the airway epithelium. Responsiveness and neutrophil numbers were determined 5 days and 1 day before ozone and 1 h after ozone (3.0 ppm, 2 h) in 6 untreated dogs and in 6 dogs treated with hydroxyurea (200 mg/kg daily for 5 days starting 5 days before ozone). In untreated dogs, responsiveness and neutrophil numbers 5 days and 1 day before ozone did not change, but responsiveness and epithelial neutrophils increased markedly after ozone. In treated dogs, circulating neutrophils decreased from 8.9 +/- 2.2 to 0.6 +/- 0.01 X 10(3) per mm3 (mean +/- SEM), and responsiveness before ozone did not change. Furthermore, increases in responsiveness and epithelial neutrophils did not occur after ozone. Six wk after stopping hydroxyurea, responsiveness and epithelial neutrophils increased markedly after ozone. The results suggest that ozone-induced hyperresponsiveness may depend on the mobilization of neutrophils into the airways.

O'Byrne, P.M.; Walters, E.H.; Gold, B.D.; Aizawa, H.A.; Fabbri, L.M.; Alpert, S.E.; Nadel, J.A.; Holtzman, M.J.

1984-08-01

70

Dopamine D2-receptor knockout mice are protected against dopaminergic neurotoxicity induced by methamphetamine or MDMA.  

PubMed

Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA), amphetamine derivatives widely used as recreational drugs, induce similar neurotoxic effects in mice, including a marked loss of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum. Although the role of dopamine in these neurotoxic effects is well established and pharmacological studies suggest involvement of a dopamine D2-like receptor, the specific dopamine receptor subtype involved has not been determined. In this study, we used dopamine D2 receptor knock-out mice (D2R(-/-)) to determine whether D2R is involved in METH- and MDMA-induced hyperthermia and neurotoxicity. In wild type animals, both drugs induced marked hyperthermia, decreased striatal dopamine content and TH- and DAT-immunoreactivity and increased striatal GFAP and Mac-1 expression as well as iNOS and interleukin 15 at 1 and 7days after drug exposure. They also caused dopaminergic cell loss in the SNpc. Inactivation of D2R blocked all these effects. Remarkably, D2R inactivation prevented METH-induced loss of dopaminergic neurons in the SNpc. In addition, striatal dopamine overflow, measured by fast scan cyclic voltammetry in the presence of METH, was significantly reduced in D2R(-/-) mice. Pre-treatment with reserpine indicated that the neuroprotective effect of D2R inactivation cannot be explained solely by its ability to prevent METH-induced hyperthermia: reserpine lowered body temperature in both genotypes, and potentiated METH toxicity in WT, but not D2R(-/-) mice. Our results demonstrate that the D2R is necessary for METH and MDMA neurotoxicity and that the neuroprotective effect of D2R inactivation is independent of its effect on body temperature. PMID:21303698

Granado, Noelia; Ares-Santos, Sara; Oliva, Idaira; O'Shea, Esther; Martin, Eduardo D; Colado, M Isabel; Moratalla, Rosario

2011-06-01

71

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: gary.miller@emory.edu

2006-03-15

72

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

PubMed

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

2014-06-01

73

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

PubMed Central

Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens (NAc). In the past, different techniques have targeted dopamine levels in the NAc to establish a basal concentration. In this study we used in vivo fast scan cyclic voltammetry (FSCV) in the NAc of awake, freely moving rats. The experiments were primarily designed to capture changes in dopamine due to phasic firing – that is, the measurement of dopamine ‘transients’. These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc. A series of experiments were designed to probe regulation of extracellular dopamine. Lidocaine was infused into the ventral tegmental area, the site of dopamine cell bodies, to arrest neuronal firing. While there was virtually no instantaneous change in dopamine concentration, longer sampling revealed a decrease in dopamine transients and a time-averaged decrease in the extracellular level. Dopamine transporter (DAT) inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc. To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter (VMAT2) inhibitor, tetrabenazine, to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals. Tetrabenazine almost abolished phasic dopamine release but increased extracellular dopamine to ~500 nM, presumably by inducing reverse transport by DAT. Taken together, data presented here show that average extracellular dopamine in the NAc is low (20–30 nM) and largely arises from phasic dopamine transients.

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

2012-01-01

74

Isoliquiritigenin suppresses cocaine-induced extracellular dopamine release in rat brain through GABA(B) receptor.  

PubMed

Glycyrrhizae radix (licorice) comprises a variety of flavonoids as major constituents including isoliquiritigenin, liquiritin, liquiritigenin, and glycyrrihizin. It has shown various biological activities such as anti-inflammatory, anti-carcinogenic and antihistamic. As very little is known in regard to drug addiction, we carried out a study on the effect of G. radix and its active component, isoliquiritigenin, on acute cocaine-induced extracellular dopamine release in moving rats. Male Sprague-Dawley rats were orally administered with methanolic extracts of G. radix or isoliquiritigenin 1 h prior to an injection of cocaine (20 mg/kg, intraperitoneal (i.p.)). Extracellular dopamine was measured by in vivo microdialysis. Extract of G. radix and isoliquiritigenin inhibited cocaine-induced extracellular dopamine level in the nucleus accumbens by dose-dependent manner. Inhibition of dopamine release by isoliquiritigenin resulted in attenuation of the expression of c-Fos, an immediately early gene induced by cocaine. Effect of isoliquiritigenin was completely prevented by a GABA(B) receptor antagonist. Thus, these results showed that G. radix and isoliquiritigenin inhibit cocaine-induced dopamine release by modulating GABA(B) receptor, suggesting that isoliquiritigenin might be effective in blocking the reinforcing effects of cocaine. PMID:18495107

Jang, Eun Young; Choe, Eun Sang; Hwang, Meeyul; Kim, Sang Chan; Lee, Jong Rok; Kim, Sang Geon; Jeon, Jae-Pil; Buono, Russell J; Yang, Chae Ha

2008-06-10

75

Methamphetamine-Induced Degeneration of Dopaminergic Neurons Involves Autophagy and Upregulation of Dopamine Synthesis  

Microsoft Academic Search

Methamphetamine (METH) selectively injures the neurites of dopamine (DA) neurons, generally without inducing cell death. It has been proposed that METH-induced redistribution of DA from the vesicular storage pool to the cytoplasm, where DA can oxidize to produce quinones and additional reactive oxygen species, may account for this selective neurotoxicity. To test this hypothesis, we used mice heterozygous (\\/) or

Kristin E. Larsen; Edward A. Fon; Teresa G. Hastings; Robert H. Edwards; David Sulzer

2002-01-01

76

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.

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

2014-01-01

77

Dopamine-induced silica-polydopamine hybrids with controllable morphology.  

PubMed

Novel silica-polydopamine hybrids, with controllable morphology, are facilely fabricated in an emulsion system consisting of tetraethyl orthosilicate, dopamine, water, and NaOH under weakly basic conditions (pH 8.5-10). An increase in initial pH favors the formation of nano-structured spherical silica-PDA hybrids from a flocculated structure. PMID:24575426

Ho, Chia-Che; Ding, Shinn-Jyh

2014-04-01

78

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

PubMed

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

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

2014-07-01

79

Nitric oxide and DOPAC-induced cell death: from GSH depletion to mitochondrial energy crisis.  

PubMed

The molecular mechanisms inherent to cell death associated with Parkinson's disease are not clearly understood. Diverse pathways, sequence of events and models have been explored in several studies. Recently, we have proposed an integrative mechanism, encompassing the interaction of nitric oxide (•NO) and a major dopamine metabolite, dihydroxyphenylacetic (DOPAC), leading to a synergistic mitochondrial dysfunction and cell death that may be operative in PD. In this study, we have studied the sequence of events underlying the mechanisms of cell death in PC12 cells exposed to •NO and DOPAC in terms of: a) free radical production; b) modulation by glutathione (GSH); c) energetic status and d) outer membrane mitochondria permeability. Using Electron Paramagnetic Resonance (EPR) it is shown the early production of oxygen free radicals followed by a depletion of GSH reflected by an increase of GSSG/GSH ratio in the cells treated with the mixture of •NO/DOPAC, as compared with the cells individually exposed to each of the stimulus. Glutathione ethyl ester (GSH-EE) and N-acetylcysteine (NAC) may rescue cells from death, increasing GSH content and preventing ATP loss in cells treated with the mixture DOPAC/•NO but failed to exert similar effects in the cells challenged only with •NO. The depletion of GSH is accompanied by a decreased activity of mitochondrial complex I. At a later stage, the concerted action of DOPAC and •NO include a rise in the ratio Bax/Bcl-2, an observation not evident when cells were exposed only to •NO. The results support a free radical-induced pathway leading to cell death involving the concerted action of DOPAC and •NO and the critical role of GSH in maintaining a functional mitochondria. PMID:21708261

Nunes, Carla; Barbosa, Rui M; Almeida, Leonor; Laranjinha, Joăo

2011-09-01

80

Erythropoietin induced erythroid precursor pool depletion causes erythropoietin hyporesponsiveness  

PubMed Central

Summary Erythropoietin (EPO) hyporesponsiveness is demonstrated by a persistence of anemia despite high dose of recombinant human erythropoietin (rHuEPO) or requirement of large doses to maintain the target hemoglobin concentration. Tolerance to rHuEPO is defined by a diminished erythropoietic response while rHuEPO concentrations are maintained at a high level. We observed a tolerance phenomenon in rats receiving multiple doses of rHuEPO. We further studied the dynamics of erythroid cells in bone marrow, spleen and blood as well as the neocytolysis of reticulocytes after a single intravenous injection of rHuEPO. The results suggest that the tolerance phenomenon observed in the peripheral blood might be due to depletion of the bone marrow precursor cells induced by rHuEPO treatment. This mechanism may be a contributing factor to the EPO hyporesponsiveness. Our findings support the dose reduction of erythropoiesis stimulating agents for patients demonstrating hyporesponsiveness.

Yan, Xiaoyu; Ait-Oudhia, Sihem; Krzyzanski, Wojciech

2013-01-01

81

Blockage of narcotic-induced dopamine receptor supersensitivity by cyclo(Leu-Gly).  

PubMed Central

We have previously reported that the administration of cyclo(Leu-Gly) to mice prior to morphinization blocked the development of tolerance to the analgesic effects of morphine as well as the development of some signs of physical dependence. In the present series of experiments, the effect of the same peptide treatment on changes in dopamine receptor sensitivity induced by chronic morphine treatment were determined. Changes in dopamine receptor sensitivity were determined by measuring (i) the effect of the dopamine agonist apomorphine on locomotor activity and (ii) the hypothermic response to another dopamine agonist, piribedil. Mice that had received the chronic morphine treatment were found to require significantly less apomorphine to produce an increase in locomotor activity, and they exhibited a significantly greater hypothermic response to piribedil than did morphine-naive mice. The injection of 0.2 mumol of cyclo(Leu-Gly) per mouse 2 hr prio to morphine treatment prevented this increased response to both dopamine agonists. Administration of the peptide after the tolerance and dependence had developed did not alter morphine tolerant and dependent states states or the enhanced response to apomorphine or piribedil. It is concluded that dopamine receptor supersensitivity may be involved in the development of narcotic tolerance and physical dependence.

Ritzmann, R F; Walter, R; Bhargava, H N; Flexner, L B

1979-01-01

82

Pramipexole inhibits MPTP toxicity in mice by dopamine D3 receptor dependent and independent mechanisms  

Microsoft Academic Search

The role of dopamine D3 receptors was investigated in mediating the neuroprotective effect of the dopamine D2\\/D3 receptor agonist (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (pramipexole) in vivo. Pramipexole retained the ability to inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion in mice in which the dopamine D3 receptor had been deleted. However, the neuroprotective efficacy was reduced in the dopamine D3 receptor-deleted mice compared to that in

Andres D. Ramirez; Stephen K.-F. Wong; Frank S. Menniti

2003-01-01

83

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.

Park, Ariane; Stacy, Mark

2011-01-01

84

Microdialysis and SPECT measurements of amphetamine-induced dopamine release in nonhuman primates  

Microsoft Academic Search

The competition between endogenous transmitters and radiolabeled ligands for in vivo binding to neuroreceptors might provide a method to measure endogenous transmitter release in the living human brain with noninvasive techniques such as positron emission tomography (PET) or single photon emission computerized tomography (SPECT). In this study, we validated the measure of amphetamine-induced dopamine release with SPECT in nonhuman primates.

Marc Laruelle; Raj N. Iyer; Mohammed S. Al-Tikriti; Yolanda Zea-Ponce; Robert Malison; Sami S. Zoghbi; Ronald M. Baldwin; Hank F. Kung; Dennis S. Charney; Paul B. Hoffer; Robert B. Innis; Charles W. Bradberry

1997-01-01

85

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

PubMed

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

2014-08-01

86

Methamphetamine-Induced Dopamine-Independent Alterations in Striatal Gene Expression in the 6-Hydroxydopamine Hemiparkinsonian Rats  

PubMed Central

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

Cadet, Jean Lud; Brannock, Christie; Krasnova, Irina N.; Ladenheim, Bruce; McCoy, Michael T.; Chou, Jenny; Lehrmann, Elin; Wood, William H.; Becker, Kevin G.; Wang, Yun

2010-01-01

87

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

PubMed

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

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

2014-04-29

88

Fate Mapping and Lineage Analyses Demonstrate the Production of a Large Number of Striatal Neuroblasts after TGF? and Noggin Striatal Infusions into the Dopamine-depleted Striatum  

PubMed Central

Infusion of TGF? into the adult dopamine (DA)-depleted striatum generates a local population of nestin+/PCNA+ newborn cells [1]. The precise origin and fate of these new striatal cells are unknown, making it difficult to direct them for neural repair in Parkinson’s disease (PD). Experiments in rats using BrdU to label neural progenitor cells (NPCs) showed that during TGF? infusion in the DA-depleted striatum, newborn striatal cells formed a homogenous population of precursors, with the majority coexpressing nestin, Mash1, Olig2 and EGFR, consistent with the phenotype of multipotent C cells. Upon TGF? pump withdrawal, the subventricular zone (SVZ) was repopulated by neuroblasts. Strikingly, during this period, numerous clusters of DCX+/PSANCAM+ neuroblasts were also produced in the ipsilateral medial striatum. In parallel, striatal BrdU+/GFAP+ astrocytes were generated, but no BrdU+/O4+/CNPase+ oligodendrocytes. Infusion of the neuralizing BMP antagonist noggin after TGF? pump withdrawal increased the neuroblast to astrocyte ratio among new striatal cells by blocking glial differentiation, but did not alter striatal neurogenesis. At no time or no treatment condition were differentiated neurons generated, including DA neurons. Using 6-OHDA lesioned nestin-CreERT2/R26R-YFP mice that allow genetic fate-mapping of SVZ nestin+ cells, we show that TGF?-generated striatal cells originate from SVZ nestin+ precursors that confirmed data from the rats on the phenotype and fate of striatal nestin+/PCNA+ cells upon TGF? withdrawal. This work demonstrates that a large population of multipotent striatal C-like cells can be generated in the DA-depleted striatum that do not spontaneously differentiate into DA neurons.

de Chevigny, Antoine; Cooper, Oliver; Vinuela, Angel; Reske-Nielsen, Casper; Lagace, Diane C.; Eisch, Amelia J.; Isacson, Ole

2008-01-01

89

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.

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

2008-01-01

90

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.

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

2011-01-01

91

Glutathione depletion in nigrostriatal slice cultures: GABA loss, dopamine resistance and protection by the tetrahydrobiopterin precursor sepiapterin  

Microsoft Academic Search

Dopaminergic neurons in culture are preferentially resistant to the toxicity of glutathione (GSH) depletion. This effect may be due to high intrinsic levels of tetrahydrobiopterin (BH4). Here we studied the effects of manipulating GSH and\\/or BH4 levels on selective neurotoxicity in organotypic nigrostriatal slice cultures. Following treatments with l-buthionine sulfoximine (BSO, 10–100 ?M, 2 days exposure, 2 days recovery), either

Jan Bert Gramsbergen; Mats Sandberg; Annette Mřller Dall; Brian Kornblit; Jens Zimmer

2002-01-01

92

A role for dopamine D1-like receptors in acute food deprivation-induced reinstatement of heroin seeking in rats  

PubMed Central

Dopamine has a critical role in drug reinforcement and the reinstatement of drug seeking due to priming or exposure to drug-associated cues. In contrast, the role of dopamine in stress-induced reinstatement is not clear. We have previously demonstrated that acute food deprivation, a clinically relevant stressor, reinstates heroin seeking in rats via a leptin-dependent mechanism. Recent reports have suggested a modulating role for leptin on dopamine transmission and drug-related behaviours. Thus, here we investigated the role of dopamine in acute food deprivation-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin (0.05 mg/kg per infusion) for 10 d. Following training, heroin seeking was extinguished and rats were tested for 48-h food deprivation-induced reinstatement while pretreated with the dopamine D1-, D2-, or D3-like receptor antagonists: SCH 23390 (0.0, 5.0 or 10.0 ?g/kg), raclopride (0.0, 50.0 or 100.0 ?g/kg) or NGB2904 (0.0, 0.1 or 5.0 ?g/kg), respectively. The dopamine D1-like receptor antagonist, SCH 23390, but neither of the other antagonists, showed a dose-dependent attenuation of food deprivation-induced reinstatement. Our results suggest that acute food deprivation-induced reinstatement may be mediated, at least in part, by activation of the dopamine D1-like receptor.

Tobin, Stephanie; Newman, Amy H.; Quinn, Tammie; Shalev, Uri

2009-01-01

93

Tyrosine hydroxylase and dopamine transporter expression in lactotrophs from postlactating rats: involvement in dopamine-induced apoptosis.  

PubMed

Cessation of lactation causes a massive loss of surplus lactotrophs in the rat pituitary gland. The factors and mechanisms involved in this phenomenon have not yet been elucidated. Besides its inhibitory control on prolactin secretion and lactotroph proliferation, evidence suggests that dopamine (DA) may be a proapoptotic factor for lactotrophs. We therefore tested the proapoptotic effect of DA on pituitary glands from virgin, lactating, and postlactating rats. By measuring mitochondrial membrane potential loss, caspase-3 activation, and nuclear fragmentation, we show that DA induces apoptosis specifically in lactotrophs from postlactating rats. We then determined that this effect was partly mediated by the DA transporter (DAT) rather than the D(2) receptor, as corroborated by the detection of DAT expression exclusively in lactotrophs from postlactating rats. We also observed tyrosine hydroxylase (TH) expression in postlactating lactotrophs that was accompanied by an increase in DA content in the anterior pituitary gland of postlactating compared with virgin rats. Finally, we observed that cells expressing TH coexpressed DAT and cleaved caspase-3. These findings show that DA may play a role in lactotroph regression during the postlactation period by inducing apoptosis. The fact that this process requires DAT and TH expression by lactotrophs themselves suggests that it may be "autocrine" in nature. PMID:17363452

Jaubert, Arnaud; Drutel, Guillaume; Leste-Lasserre, Thierry; Ichas, François; Bresson-Bepoldin, Laurence

2007-06-01

94

Gastric mucosal lesions induced by complete dopamine system failure in rats. The effects of dopamine agents, ranitidine, atropine, omeprazole and pentadecapeptide BPC 157  

Microsoft Academic Search

Up to now, for gastric lesions potentiation or induction, as well as determination of endogenous dopamine significance, dopamine antagonist or dopamine vesicle depletor were given separately. Therefore, without combination studies, the evidence for dopamine significance remains split on either blockade of dopamine post-synaptic receptor or inhibition of dopamine storage, essentially contrasting with endogenous circumstances, where both functions could be simultaneously

Pedrag Sikiric; Jadranka Šeparovic; Gojko Buljat; Tomislav Anic; Dinko Stancic-Rokotov; Darko Mikus; Bozidar Duplancic; Anton Marovic; Ivan Zoricic; Ingrid Prkacin; Martina Lovric-Bencic; Gorana Aralica; Tihomil Ziger; Darko Perovic; Nikola Jelovac; Goran Dodig; Ivo Rotkvic; Stjepan Mise; Sven Seiwerth; Branko Turkovic; Zeljko Grabarevic; Marijan Petek; Rudolf Rucman

2000-01-01

95

Ethanol-Induced Depletion of Cerebellar Guanosine 3',5'-Cyclic Monophosphate Levels.  

National Technical Information Service (NTIS)

Single doses of ethanol induce a severe depletion (95 percent) of cerebellar guanosine 3-5-cyclic monophosphate (C-GMP) levels within 1 hour after administration. The degree of this depletion is a function of the amount of ethanol in the blood. Interactio...

J. D. Redos G. N. Catravas W. A. Hunt

1976-01-01

96

Numerical study on thermal-induced lubricant depletion in laser heat-assisted magnetic recording systems  

Microsoft Academic Search

This paper presents a numerical investigation of heat transfer and lubricant depletion on the hard disk in a heat-assisted magnetic recording (HAMR) system. The heat is induced by a laser pulse shooting down from a slider flying over the disk coated with a thin layer of lubricant. The main mechanisms to cause the lubricant depletion are examined by taking into

Yan Zeng; Weidong Zhou; Xiaoyang Huang; Shengkai Yu

97

Mechanism of 1-methyl-4-phenylpyridinium-induced dopamine release from PC12 cells.  

PubMed

The molecular mechanism of 1-methyl-4-phenylpyridinium (MPP+), a Parkinsonism-inducing neurotoxin, has been studied in PC12 cells. The cells treated with MPP+ (100 microM) induced a rapid increase in phosphorylation of tyrosine residues of several proteins, including synaptophysin, a major 38 kDa synaptic vesicle protein implicated in exocytosis. An accelerated release of dopamine by MPP+ correlated with phosphorylation of synaptophysin. Exposing the cells to MPP+ triggered reactive oxygen species (ROS) generation within 60 min of treatment and the said effect was blocked by mazindol, a dopamine uptake blocker. In addition, pretreatment with 50-100 microM of selegiline, a selective MAO-B inhibitor, significantly suppressed MPP+-mediated ROS generation. These effects of MPP+ result in the generation of ROS, which may be involved in neuronal degeneration seen in Parkinson's disease. PMID:16176067

Chagkutip, Jaturaporn; Govitrapong, Piyarat; Klongpanichpak, Sirirat; Ebadi, Manuchair

2005-05-01

98

Reversal of stress-induced anhedonia by the dopamine receptor agonist, pramipexole  

Microsoft Academic Search

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of a palatable (1%) sucrose solution, and to attenuate food-induced place preference conditioning. In this study the effects of pramipexole (SND-919), a dopamine D2 agonist, were studied during 7–9 weeks of chronic treatment. Pramipexole (1.0 mg\\/kg per day) reversed the suppression of sucrose intake in stressed

Paul Willner; Spiros Lappas; Survjit Cheeta; Richard Muscat

1994-01-01

99

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

2009-01-01

100

The decrease in hypothalamic dopamine secretion induced by suckling: comparison of voltammetric and radioisotopic methods of measurement. [Rats  

SciTech Connect

Previous in situ voltammetric microelectrode measurements of median eminence dopamine release during mammary nerve stimulation of anesthetized lactating rats revealed a transient (1-3 min) 70% decline of dopamine concentrations. This dopamine was believed to be destined for secretion into the hypophysial portal circulation, but direct experimental support for this supposition was lacking. Thus, in the present study, (3H)dopamine release into brief sequential samples of hypophysial portal blood was compared with dopamine release in the median eminence measured by voltammetry. Lactating female rats were urethane anesthetized, and the median eminence pituitary region was exposed. (3H)Tyrosine was injected into a jugular cannula (100 microCi) followed by continuous infusion (5 microCi/min). In a preliminary experiment, this regimen produced a steady state level of (3H)dopamine in the portal blood within 45 min. In subsequent experiments, portal blood was collected as sequential 3-min samples, and electrochemical sampling from a microelectrode placed in the median eminence occurred at 1-min intervals. Electrochemical current resulting from the oxidation of dopamine in the medial median eminence was unvarying throughout the 75-min experiment in control rats (n . 4) and during the 30-min control period preceding mammary nerve stimulation in the other group (n . 4). These results were paralled by (3H) dopamine levels in portal blood during the same periods of time. All animals showed simultaneous decreases in oxidation current and (3H)dopamine levels within 1-4 min after initiation of mammary nerve stimulation. These and earlier results demonstrate that mammary nerve stimulation (and by extension, suckling) induces a momentary, but profound, decrease in hypothalamic dopamine secretion which precedes or accompanies the rise in PRL secretion evoked by the same stimulus.

Plotsky, P.M.; Neill, J.D.

1982-03-01

101

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

PubMed

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

2014-01-01

102

Suppression of histamine-induced tachypnoea in the rhesus monkey by sibenadet: no role for dopamine D2 receptors.  

PubMed

1. Sibenadet (Viozan), a dual dopamine D(2)/beta(2)-adrenoceptor agonist, suppresses histamine-induced tachypnoea in the dog by activating dopamine D(2) receptors. We here compare the effects of sibenadet and formoterol, a selective beta(2)-adrenoceptor agonist, on histamine-induced tachypnoea in the rhesus monkey. 2. Anaesthetized, spontaneously breathing, rhesus monkeys were set up for measuring airways resistance, respiratory rate, blood pressure and heart rate. 3. Both sibenadet and formoterol administered by aerosol, induced inhibition of the bronchoconstrictor response to aerosolized methacholine accompanied by tachycardia. Sibenadet, but not formoterol, also reduced blood pressure. 4. Administration of histamine by inhalation induced tachypnoea which was accompanied by bronchoconstriction. Tachypnoea to histamine was suppressed by both sibenadet and formoterol at doses which manifest anti-bronchoconstrictor activity. These effects and the accompanying tachycardia but not the hypotension induced by sibenadet were abolished by pretreatment with propranolol. 5. The dopamine D(2) receptor agonist, quinagolide, did not suppress tachypnoea to histamine despite inducing a fall in blood pressure indicating activation of dopamine D(2) receptors. 6. Thus, both sibenadet and formoterol suppress histamine-evoked tachypnoea in the rhesus monkey. The effect arises exclusively through activation of beta(2)-adrenoceptors and probably reflects the anti-bronchoconstrictor effects of these agents. The results reveal a fundamental difference in the role of dopamine receptors in the airways of dog and rhesus monkey. PMID:15307823

Fozard, J R; Buescher, H; Farr, D C; Mazzoni, L

2004-01-01

103

Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex  

Microsoft Academic Search

Summary Brain dopamine is implicated in the regulation of move- ment, attention, reward and learning. Dysfunction of dopamine plays a role in Parkinson's disease, schizo- phrenia and drug addiction. It is released in the stria- tum when dopamine neurons in the midbrain undergo burst firing. Several animal studies have shown that dopamine can also be released under direct control of

Antonio P. Strafella; Maria Fraraccio; Alain Dagher

2003-01-01

104

N-oleoyl-dopamine decreases muscle rigidity induced by reserpine in rats.  

PubMed

N-oleoyl-dopamine (OLDA), a product of condensation of oleic acid and dopamine (DA), is a bioactive compound that crosses the blood-brain barrier after systemic administration. The possibility arises that OLDA could have a potential role in treating DA-related disorders, such as Parkinsons disease (PD). In the present study we seek to determine whether OLDA would affect muscle tone and akinesia in two rat models of PD: the reserpine-evoked muscle rigidity and the reserpine- and haloperidol-induced catalepsy. We found that OLDA (20 mg/kg) significantly decreased muscle rigidity induced by reserpine (2.5 mg/kg), measured as an increased mechanical muscle resistance (MMG) in response to a passive extension and flexion of a rat hind limb at the ankle joint. Moreover, OLDA potently decreased the reserpine-enhanced tonic and reflex electromyographic (EMG) activities recorded before and during the movement, respectively. A lower dose of OLDA (10 mg/kg) failed to have appreciable effects. The reference compound L-DOPA (25 mg/kg) also attenuated the reserpine-increased MMG and EMG activities; the effects were, however, observed much later and were less prominent than those characteristic of OLDA. In contrast to the effects on muscle tone, OLDA (20 and 40 mg/kg) did not influence catalepsy induced by either reserpine (1.25 mg/kg) or haloperidol (0.5 mg/kg). In conclusion, the study demonstrates a novel biological action of N-oleoyl-dopamine consisting of lowering the reserpine-induced muscle rigidity. However, the lack of influence on akinesia suggests that the compound has myorelaxant rather than anti-Parkinsonian properties. PMID:19309549

Konieczny, J; Przegalinski, E; Pokorski, M

2009-01-01

105

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

PubMed

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

2013-10-01

106

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

Microsoft Academic Search

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

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

2007-01-01

107

Uptake inhibitors but not substrates induce protease resistance in extracellular loop two of the dopamine transporter.  

PubMed

Changes in protease sensitivity of extracellular loop two (EL2) of the dopamine transporter (DAT) during inhibitor and substrate binding were examined using trypsin proteolysis and epitope-specific immunoblotting. In control rat striatal membranes, proteolysis of DAT in a restricted region of EL2 was produced by 0.001 to 10 microg/ml trypsin. However, in the presence of the dopamine uptake blockers [2-(diphenylmethoxyl) ethyl]-4-(3phenylpropyl) piperazine (GBR 12909), mazindol, 2beta-carbomethoxy-3beta-(4-flourophenyl)tropane (beta-CFT), nomifensine, benztropine, or (-)-cocaine, 100- to 1000-fold higher concentrations of trypsin were required to produce comparable levels of proteolysis. Protease resistance induced by ligands was correlated with their affinity for DAT binding, was not observed with Zn2+, (+)-cocaine, or inhibitors of norepinephrine or serotonin transporters, and was not caused by altered catalytic activity of trypsin. Together, these results support the hypothesis that the interaction of uptake inhibitors with DAT induces a protease-resistant conformation in EL2. In contrast, binding of substrates did not induce protease resistance in EL2, suggesting that substrates and inhibitors interact with DAT differently during binding. To assess the effects of EL2 proteolysis on DAT function, the binding and transport properties of trypsin-digested DAT were assayed with [3H]CFT and [3H]dopamine. Digestion decreased the Bmax for binding and the Vmax for uptake in amounts that were proportional to the extent of proteolysis, indicating that the structural integrity of EL2 is required for maintenance of both DAT binding and transport functions. Together this data provides novel information about inhibitor and substrate interactions at EL2, possibly relating the protease resistant DAT conformation to a mechanism of transport inhibition. PMID:14978248

Gaffaney, Jon D; Vaughan, Roxanne A

2004-03-01

108

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

PubMed

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

2014-01-01

109

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.

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

2014-01-01

110

Repeated exposure to MDMA provides neuroprotection against subsequent MDMA-induced serotonin depletion in brain  

PubMed Central

Repeated exposure to sub-lethal insults has been reported to result in neuroprotection against a subsequent deleterious insult. The purpose of this study was to evaluate whether repeated exposure (preconditioning) to a non-5-HT depleting dose of MDMA in adult rats provides neuroprotection against subsequent MDMA induced 5-HT depletion. Treatment of rats with MDMA (10 mg/kg, ip every 2 hrs for 4 injections) resulted in a 50-65% depletion of 5-HT in the striatum, hippocampus and cortex, and these depletions were significantly attenuated in rats that received a preconditioning regimen of MDMA (10 mg/kg, ip daily for 4 days). The 5-HT depleting regimen of MDMA also resulted in a 40-80% reduction in 5-HT transporter immunoreactivity (SERTir), and the reduction in SERTir also was completely attenuated in MDMA preconditioned animals. Preconditioning with MDMA (10 mg/kg, i.p.) daily for 4 days provided neuroprotection against methamphetamine-induced 5-HT depletion, but not DA depletion, in the striatum. Additional studies were conducted to exclude the possibility that alterations in MDMA pharmacokinetics or MDMA induced hyperthermia in rats previously exposed to MDMA contributes towards neuroprotection. During the administration of the 5-HT depleting regimen of MDMA, there was no difference in the extracellular concentration of the drug in the striatum of rats that had received 4 prior, daily injections of vehicle or MDMA. Moreover, there was no difference in the hyperthermic response to the 5-HT depleting regimen of MDMA in rats that had earlier received 4 daily injections of vehicle or MDMA. Furthermore, hyperthermia induced by MDMA during preconditioning appears not to contribute toward neuroprotection, inasmuch as preconditioning with MDMA at a low ambient temperature at which hyperthermia was absent did not alter the neuroprotection provided by the preconditioning regimen. Thus, prior exposure to MDMA affords protection against the long-term depletion of brain 5-HT produced by subsequent MDMA administration. The mechanisms underlying preconditioning-induced neuroprotection for MDMA remain to be determined.

Bhide, Nirmal S.; Lipton, Jack; Cunningham, Jacobi; Yamamoto, Bryan K.; Gudelsky, Gary A.

2009-01-01

111

Growth hormone-induced diacylglycerol and ceramide formation via Galpha i3 and Gbeta gamma in GH4 pituitary cells. Potentiation by dopamine-D2 receptor activation.  

PubMed

Growth hormone (GH) secretion is regulated by indirect negative feedback mechanisms. To address whether GH has direct actions on pituitary cells, lipid signaling in GH(4)ZR(7) somatomammotroph cells was examined. GH (EC(50) = 5 nm) stimulated diacylglycerol (DAG) and ceramide formation in parallel by over 10-fold within 15 min and persisting for >3 h. GH-induced DAG/ceramide formation was blocked by pertussis toxin (PTX) implicating G(i)/G(o) proteins and was potentiated 1.5-fold by activation of G(i)/G(o)-coupled dopamine-D2S receptors, which had no effect alone. Following PTX pretreatment, only PTX-resistant Galpha(i)3, not Galpha(o) or Galpha(i)2, rescued GH-induced DAG/ceramide signaling. GH-induced DAG/ceramide formation was also blocked in cells expressing Gbetagamma blocker GRK-ct. In GH(4)ZR(7) cells, GH induced phosphorylation of JAK2 and STAT5, which was blocked by PTX and mimicked by ceramide analogue C2-ceramide or sphingomyelinase treatment to increase endogenous ceramide. We conclude that in GH(4) pituitary cells, GH induces formation of DAG/ceramide via a novel Galpha(i)3/Gbetagamma-dependent pathway. This novel pathway suggests a mechanism for autocrine feedback regulation by GH of pituitary function. PMID:12376552

Liu, Gele; Robillard, Liliane; Banihashemi, Behzad; Albert, Paul R

2002-12-13

112

Differences in reserpine-induced striatal dopamine output and content between female and male mice: implications for sex differences in vesicular monoamine transporter 2 function.  

PubMed

In this report a series of six in vitro experiments in which reserpine-evoked dopamine output and two in vivo experiments in which the effects of reserpine injections upon dopamine content from striatal tissue of female and male mice were performed as a means to assess possible sex differences in vesicular monoamine transporter 2 (VMAT2) function. Significantly greater amounts of dopamine were obtained from striatal tissue of female mice in response to either a brief (experiment 1) or continuous (experiment 2) infusion of reserpine. Similarly, reserpine-evoked dopamine output from striatal tissue of gonadectomized females was significantly greater that that of gonadectomized males (experiment 3). When reserpine-evoked dopamine responses were compared directly between intact versus gonadectomized females (experiment 4) or males (experiment 5) no statistically significant differences were obtained. Finally, comparisons of gonadectomized females treated or not with estrogen revealed no statistically significant differences in reserpine-evoked dopamine output (experiment 6). Injections of reserpine produced significantly greater depletions of striatal dopamine content within intact female versus male mice (experiment 7). Dopamine contents of gonadectomized females treated or not with estrogen did not differ following treatment with reserpine, but were significantly greater than that of gonadectomized males (experiment 8). Taken together, these results show that female striatal tissue is more responsive to reserpine-evoked dopamine output, and this sex difference appears to be estrogen independent. Similarly, the dopamine depleting effects of reserpine are greater in intact female mice, however, gonadectomy reverses this effect in an estrogen independent manner. The data suggest that female mice may have a greater amount/activity of VMAT2 function as revealed by the increased responsiveness to the VMAT2 blocking drug, reserpine. Such differences in VMAT2 function may be related to the gender differences observed in conditions like Parkinson's disease and drug addiction. PMID:18515015

Dluzen, D E; Bhatt, S; McDermott, J L

2008-07-17

113

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.

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

2012-01-01

114

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

PubMed Central

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

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

2012-01-01

115

Differential behavioral reinforcement effects of dopamine receptor agonists in the rat with bilateral lesion of the posterior ventral tegmental area.  

PubMed

Dopamine dysregulation syndrome in Parkinson's disease has been attributed to dopamine replacement therapies and/or a lesion of the dopaminergic system. The dopaminergic neuronal loss targets the substantia nigra and the ventral tegmental area (VTA). We hypothesize that dopamine replacement therapy is responsible for the potential reinforcement effect in Parkinson's disease by acting on the neuronal reward circuitry. Therefore this study was designed to explore the potential motivational effect of dopamine replacement therapy in bilateral VTA-lesioned animals. The posterior (p)VTA, which project to the nucleus accumbens (NAc) constitutes the major dopamine neuronal circuitry implicated in addictive disorders. Using the conditioned place preference (CPP) behavioral paradigm, we investigated the motivational effects of dopamine receptor agonists, and cocaine in rat with a 6-OHDA bilateral lesion of the pVTA. Amongst the dopamine receptor agonists used in this study only the D2R and D3R agonists (bromocriptine, PD128907 and pramipexole), induced a significant CPP in pVTA-lesioned animals. Dopamine receptor agonists did not induce behavioral sensitization in sham animals. Moreover, confocal D2R immunostaining analysis showed a significant increase in the number of D2R per cell body in the NAc shell of pVTA lesioned rats compared to sham. This result correlated, for the first time, the dopamine receptor agonists effect with DR2 overexpression in the NAc shell of pVTA-lesioned rats. In addition, cocaine, which is known to increase dopamine release, induced behavioral sensitization in sham group but not in dopamine deprived group. Thus, the later result highlighted the importance of pVTA-NAc dopaminergic pathway in positive reinforcements. Altogether these data suggested that the implication of the dopamine replacement therapy in the appearance of dopamine dysregulation syndrome in Parkinson's disease is probably due to both neuronal degeneration in the posterior VTA and dopamine receptor sensitization in the dopamine depleted NAc. PMID:23727149

Ouachikh, Omar; Dieb, Wisam; Durif, Franck; Hafidi, Aziz

2013-09-01

116

Role of Neurokinin-1 and Dopamine Receptors on the Striatal Methamphetamine-Induced Proliferation of New Cells in Mice  

PubMed Central

A neurotoxic dose of methamphetamine (METH) induces the loss of some striatal neurons. Interestingly, the METH-induced apoptosis in the striatum is immediately followed by the generation of new cells (cytogenesis). In the present study, we investigated the role of the neurokinin-1, dopamine D1 and D2 receptors on the METH-induced cytogenesis. To that end, male mice were given a single injection (30 mg/kg, ip) or a binge of METH (10 mg/kg, 4X at two-hour intervals, ip). BrdU (100 mg/kg, ip) was given 36 hours after the last injection of METH. Newly generated cells were detected by immunohistochemistry and cell counts were performed using unbiased computerized stereology. Either single or binge exposure to METH resulted in the generation of new cells. The single optimized dose was used for subsequent mechanistic studies. Pretreatment with the dopamine D1 receptor antagonist SCH23390 (0.1 mg/kg, ip) 30 minutes prior to METH abrogated the METH-induced striatal cytogenesis. Pretreatment with the dopamine D2 receptor antagonist raclopride (1 mg/kg, ip) failed to affect this phenomenon. Finally, pretreatment with the neurokinin-1 receptor antagonist WIN 51,708 (5 mg/kg, ip) 30 minutes prior to METH abrogated the METH-induced cytogenesis. In conclusion, neurokinin-1 and dopamine D1 receptors are required for the METH-induced striatal cytogenesis while the D2 receptor is without effect.

Tulloch, Ingrid; Ghazaryan, Nane; Mexhitaj, Ina; Ordonez, Dalila; Angulo, Jesus A.

2011-01-01

117

Role of neurokinin-1 and dopamine receptors on the striatal methamphetamine-induced proliferation of new cells in mice.  

PubMed

A neurotoxic dose of methamphetamine (METH) induces the loss of some striatal neurons. Interestingly, the METH-induced apoptosis in the striatum is immediately followed by the generation of new cells (cytogenesis). In the present study, we investigated the role of the neurokinin-1, dopamine D1 and D2 receptors on the METH-induced cytogenesis. To that end, male mice were given a single injection (30 mg/kg, ip) or a binge of METH (10mg/kg, 4× at two-hour intervals, ip). BrdU (100mg/kg, ip) was given 36 h after the last injection of METH. Newly generated cells were detected by immunohistochemistry and cell counts were performed using unbiased computerized stereology. Either single or binge exposure to METH resulted in the generation of new cells. The single optimized dose was used for subsequent mechanistic studies. Pretreatment with the dopamine D1 receptor antagonist SCH23390 (0.1mg/kg, ip) 30 min prior to METH abrogated the METH-induced striatal cytogenesis. Pretreatment with the dopamine D2 receptor antagonist raclopride (1mg/kg, ip) failed to affect this phenomenon. Finally, pretreatment with the neurokinin-1 receptor antagonist WIN 51,708 (5mg/kg, ip) 30 min prior to METH abrogated the METH-induced cytogenesis. In conclusion, neurokinin-1 and dopamine D1 receptors are required for the METH-induced striatal cytogenesis while the D2 receptor is without effect. PMID:21652034

Tulloch, Ingrid; Ghazaryan, Nane; Mexhitaj, Ina; Ordonez, Dalila; Angulo, Jesus A

2011-07-01

118

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

PubMed

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

2012-04-01

119

Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors.  

PubMed

Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction. PMID:19091987

Melis, Miriam; Pillolla, Giuliano; Luchicchi, Antonio; Muntoni, Anna Lisa; Yasar, Sevil; Goldberg, Steven R; Pistis, Marco

2008-12-17

120

An unusual case of self-induced electrolyte depletion  

PubMed Central

A case of anorexia nervosa, presenting with unexplained hypokalaemia, is described. The patient was also secretly addicted to purgatives and diuretics. During an attempted metabolic balance study she secretly disposed of food and excreta, which were smuggled from the hospital by her sister. The patient induced her husband to bring his own stools into the ward, these then being substituted for her own. The interrelationships of the electrolyte disturbances, elevation of plasma renin, renin substrate, and hyperaldosteronism are discussed, particularly in connexion with the pathogenesis of peripheral oedema in anorexia nervosa.

Love, D. R.; Brown, J. J.; Fraser, R.; Lever, A. F.; Robertson, J. I. S.; Timbury, G. C.; Thomson, Sheena; Tree, M.

1971-01-01

121

Neuroprotection against neuroblastoma cell death induced by depletion of mitochondrial glutathione.  

PubMed

Mitochondrial glutathione pool is vital in protecting cells against oxidative stress as the majority of the cellular reactive oxygen species are generated in mitochondria. Oxidative stress is implicated as a causative factor in neuronal death in neurodegenerative disorders. We hypothesized that depletion of mitochondrial glutathione leads to mitochondrial dysfunction and apoptotic death of SK-N-SH (human neuroblastoma) cells and investigated the neuroprotective strategies against GSH depletion. SK-N-SH cells were treated with two distinct inhibitors of glutathione metabolism: L-buthionine-(S, R)-sulfoximine (BSO) and ethacrynic acid (EA). EA treatment caused depletion of both the total and mitochondrial glutathione (while BSO had no effect on mitochondrial glutathione), enhanced rotenone-induced ROS production, and reduced the viability of SK-N-SH cells. Glutathione depletion by BSO or EA demonstrated positive features of mitochondria-mediated apoptosis in neuroblastoma cell death. Prevention of apoptosis by Bcl2 overexpression or use of antioxidant ebselen did not confer neuroprotection. Co-culture with U-87 (human glioblastoma) cells protected SK-N-SH cells from the cell death. Our data suggest that depletion of mitochondrial glutathione leads to mitochondrial dysfunction and apoptosis. The study indicates that preventing mitochondrial glutathione depletion could become a novel strategy for the development of neuroprotective therapeutics in neurodegenerative disorders. PMID:23494481

Dukhande, Vikas V; Kawikova, Ivana; Bothwell, Alfred L M; Lai, James C K

2013-06-01

122

Inhibition by dizocilpine (MK-801) of striatal dopamine release induced by MPTP and MPP+: possible action at the dopamine transporter.  

PubMed Central

1. The NMDA-type glutamate receptor antagonist, dizocilpine (MK-801) can protect against neurotoxicity associated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its principal metabolite, the 1-methyl-4-phenylpyridinium ion (MPP+). It has been suggested that these neurotoxic effects may be mediated by release of excitatory amino acids, but possible alternative mechanisms have been little investigated. 2. MPTP and MPP+ (0.1-1000 microM) were tested in superfused rat striatal synaptosomes preloaded with [3H]-dopamine. Both MPTP (10 microM and higher) and MPP+ (1 microM and higher) evoked an immediate and concentration-dependent release of [3H]-dopamine. The maximal effect exceeded that achievable with nicotine. For subsequent experiments, submaximal concentrations of MPTP (50 microM) and MPP+ (10 microM) were tested. 3. MK-801 (0.1-100 microM) inhibited responses to MPTP (50 microM) and MPP+ (10 microM) in a concentration-dependent manner. However, further tests of NMDA-type glutamate receptor involvement proved negative. Responses to MPTP or MPP+ were unaffected by the omission of Mg2+ or Ca2+ and were not reduced by the NMDA receptor antagonists, AP-7 (200 microM) and kynurenic acid (300 microM). In this assay, N-methyl-D-aspartate (even in the absence of Mg2+ and with added glycine and strychnine) did not evoked [3H]-dopamine release. 4. In crude membrane preparations of rat cerebral cortex, MPTP and MPP+ inhibited high-affinity [3H]-nicotine binding to nicotinic cholinoceptors (IC50 1.8 microM and 26 microM, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Clarke, P B; Reuben, M

1995-01-01

123

Insulin induces long-term depression of VTA dopamine neurons via an endocannabinoid-mediated mechanism  

PubMed Central

The prevalence of obesity has drastically increased over the last few decades. Exploration into how hunger and satiety signals influence the reward system can help us to understand non-homeostatic mechanisms of feeding. Evidence suggests that insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce a long-term depression (LTD) of excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high fat meal, which elevates endogenous insulin levels, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior and conditioned place preference for food. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces salience of food-related cues.

Labouebe, Gwenael; Liu, Shuai; Dias, Carine; Zou, Haiyan; Wong, Jovi C.Y.; Karunakaran, Subashini; Clee, Susanne M.; Phillips, Anthony; Boutrel, Benjamin; Borgland, Stephanie L.

2014-01-01

124

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

1994-01-01

125

Is there a role for nitric oxide in methamphetamine-induced dopamine terminal degeneration?  

PubMed

Methamphetamine (METH) abuse results in long-term damage to the dopaminergic system, manifesting as decreases in dopamine (DA) tissue content, DA transporter binding, as well as tyrosine hydroxylase and vesicular monoamine transporter immunostaining. However, the exact cascade of events that ultimately result in this damage has not been clearly elucidated. One factor that has been heavily implicated in METH-induced DA terminal degeneration is the production of nitric oxide (NO). Unfortunately, many of the studies attempting to clarify the role of NO in METH-induced neurotoxicity have been confounded by issues such as the disruption of METH-induced hyperthermia, preventing the formation of strong conclusions. As a result, there is a body of work suggesting that NO is sufficient for METH-induced neurotoxicity, while other studies suggest that NO does not play a role in METH-induced degeneration of DA nerve terminals. This review summarizes the existing studies investigating the role of NO in METH-induced neurotoxicity, and argues that while NO may be necessary for METH-induced neurotoxicity, it is not sufficient. Finally, important areas of future investigation are highlighted and discussed. PMID:23918001

Friend, Danielle M; Fricks-Gleason, Ashley N; Keefe, Kristen A

2014-02-01

126

Epigenetic dysregulation of the dopamine system in diet-induced obesity.  

PubMed

Chronic intake of high-fat (HF) diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to HF diet have been observed in the hypothalamus, important in the homeostatic control of food intake, as well as within the central reward circuitry [ventral tegmental area (VTA), nucleus accumbens (NAc), and pre-frontal cortex (PFC)], critical for coding the rewarding properties of palatable food and important in hedonically driven feeding behavior. Using a mouse model of diet-induced obesity (DIO), significant alterations in the expression of DA-related genes were documented in adult animals, and the general pattern of gene expression changes was opposite within the hypothalamus versus the reward circuitry (increased vs. decreased, respectively). Differential DNA methylation was identified within the promoter regions of tyrosine hydroxylase (TH) and dopamine transporter (DAT), and the pattern of this response was consistent with the pattern of gene expression. Behaviors consistent with increased hypothalamic DA and decreased reward circuitry DA were observed. These data identify differential DNA methylation as an epigenetic mechanism linking the chronic intake of HF diet with altered DA-related gene expression, and this response varies by brain region and DNA sequence. PMID:22220805

Vucetic, Zivjena; Carlin, Jesse Lea; Totoki, Kathy; Reyes, Teresa M

2012-03-01

127

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

2012-01-01

128

Cholesterol depletion inhibits electrophysiological changes induced by anoxia in CA1 region of rat hippocampal slices.  

PubMed

The hyper-activation of glutamate receptors is a key event in the degenerative processes triggered by ischemia in the brain. Several types of these receptors reside in cholesterol-sphingomyelin rich domains of post-synaptic plasma membranes and have been described to be sensitive to cholesterol depletion. Hence we investigated, by extracellular recordings, the effect of cholesterol depletion on population spikes (PS) during ischemia-like conditions in the CA1 region of rat hippocampal slices using the cholesterol-depleting agent methyl-beta-cyclodextrin (MbetaCD). Results obtained demonstrate that MbetaCD prevents the changes induced by anoxic insult, i.e., depression of the population spike amplitude and insurgence of ischemic long-term potentiation. Furthermore cholesterol depletion prevents the disappearance of population spike induced by anoxia/aglycemia during kainate perfusion. Our data suggest a possible role of MbetaCD in preventing the pathological changes in synaptic activity induced by ischemia and indicate that manipulation of lipid components of membrane rafts might provide a new approach for the treatment of ischemia. PMID:19699721

Rufini, Stefano; Grossi, Daniele; Luly, Paolo; Tancredi, Virginia; Frank, Claudio; D'Arcangelo, Giovanna

2009-11-17

129

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.

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

2010-01-01

130

Pramipexole inhibits MPTP toxicity in mice by dopamine D3 receptor dependent and independent mechanisms.  

PubMed

The role of dopamine D3 receptors was investigated in mediating the neuroprotective effect of the dopamine D2/D3 receptor agonist (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (pramipexole) in vivo. Pramipexole retained the ability to inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion in mice in which the dopamine D3 receptor had been deleted. However, the neuroprotective efficacy was reduced in the dopamine D3 receptor-deleted mice compared to that in littermates expressing the wildtype receptor. Furthermore, the dopamine D3 receptor selective antagonist 2-(3-[4-(2-tert-butyl-6-trifluoromethyl-4-pyrimidinyl)-1-piperazinyl]propylthio)-4-pyrimidinol (A-437203) partially inhibited the neuroprotective effect of pramipexole in dopamine D3 receptor expressing mice but not in receptor-deleted mice. These results indicate that pramipexole protects dopamine neurons from MPTP-induced toxicity by mechanisms that are both dependent and independent of an interaction with dopamine D3 receptors. PMID:12954356

Ramirez, Andres D; Wong, Stephen K-F; Menniti, Frank S

2003-08-15

131

Dopamine-Dependent Compensation Maintains Motor Behavior in Mice with Developmental Ablation of Dopaminergic Neurons  

PubMed Central

The loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and consequent depletion of striatal dopamine are known to underlie the motor deficits observed in Parkinson's disease (PD). Adaptive changes in dopaminergic terminals and in postsynaptic striatal neurons can compensate for significant losses of striatal dopamine, resulting in preservation of motor behavior. In addition, compensatory changes independent of striatal dopamine have been proposed based on PD therapies that modulate nondopaminergic circuits within the basal ganglia. We used a genetic strategy to selectively destroy dopaminergic neurons in mice during development to determine the necessity of these neurons for the maintenance of normal motor behavior in adult and aged mice. We find that loss of 90% of SNc dopaminergic neurons and consequent depletion of >95% of striatal dopamine does not result in changes in motor behavior in young-adult or aged mice as evaluated by an extensive array of motor behavior tests. Treatment of aged mutant mice with the dopamine receptor antagonist haloperidol precipitated motor behavior deficits in aged mutant mice, indicating that <5% of striatal dopamine is sufficient to maintain motor function in these mice. We also found that mutant mice exhibit an exaggerated response to l-DOPA compared with control mice, suggesting that preservation of motor function involves sensitization of striatal dopamine receptors. Our results indicate that congenital loss of dopaminergic neurons induces remarkable adaptions in the nigrostriatal system where limited amounts of dopamine in the dorsal striatum can maintain normal motor function.

DeMaro, Joseph A.; Knoten, Amanda; Hoshi, Masato; Pehek, Elizabeth; Johnson, Eugene M.; Gereau, Robert W.

2013-01-01

132

B Cell Depletion Reduces the Number of Autoreactive T Helper Cells and Prevents Glucose-6-Phosphate Isomerase-Induced Arthritis  

PubMed Central

The therapeutic benefit of B cell depletion in patients with rheumatoid arthritis has provided proof of concept that B cells are relevant for the pathogenesis of arthritis. It remains unknown which B cell effector functions contribute to the induction or chronification of arthritis. We studied the clinical and immunological effects of B cell depletion in glucose-6-phosphate isomerase-induced arthritis. We targeted CD22 to deplete B cells. Mice were depleted of B cells before or after immunization with glucose-6-phosphate isomerase (G6PI). The clinical and histological effects were studied. G6PI-specific antibody responses were measured by ELISA. G6PI-specific T helper (Th) cell responses were assayed by polychromatic flow cytometry. B cell depletion prior to G6PI-immunization prevented arthritis. B cell depletion after immunization ameliorated arthritis, whereas B cell depletion in arthritic mice was ineffective. Transfer of antibodies from arthritic mice into B cell depleted recipients did not reconstitute arthritis. B cell depleted mice harbored much fewer G6PI-specific Th cells than control animals. B cell depletion prevents but does not cure G6PI-induced arthritis. Arthritis prevention upon B cell depletion is associated with a drastic reduction in the number of G6PI-specific effector Th cells.

Morawietz, Lars; Dunussi-Joannopoulos, Kyri; Kamradt, Thomas

2011-01-01

133

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

PubMed

The neurological effects of organophosphate (OP) 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 (CPF) on dopamine and glutamatergic neurotransmission effectors in corticostriatal motor/reward circuitry. CPF potentiated protein kinase A (PKA)-dependent phosphorylation of the striatal protein dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP-32) and the glutamate receptor 1 (GluR1) subunit of ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (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 N,N-diethyl-meta-toluamide (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 M; O'Callaghan, James P; Bibb, James A

2011-10-01

134

Reduced vesicular storage of dopamine exacerbates methamphetamine-induced neurodegeneration and astrogliosis  

PubMed Central

The vesicular monoamine transporter 2 (VMAT2) controls the loading of dopamine (DA) into vesicles and therefore determines synaptic properties such as quantal size, receptor sensitivity, and vesicular and cytosolic DA concentration. Impairment of proper DA compartmentalization is postulated to underlie the sensitivity of DA neurons to oxidative damage and degeneration. It is known that DA can auto-oxidize in the cytosol to form quinones and other oxidative species and that this production of oxidative stress is thought to be a critical factor in DA terminal loss after methamphetamine (METH) exposure. Using a mutant strain of mice (VMAT2 LO), which have only 5–10% of the VMAT2 expressed by wild-type animals, we show that VMAT2 is a major determinant of METH toxicity in the striatum. Subsequent to METH exposure, the VMAT2 LO mice show an exacerbated loss of dopamine transporter and tyrosine hydroxylase (TH), as well as enhanced astrogliosis and protein carbonyl formation. More importantly, VMAT2 LO mice show massive argyrophilic deposits in the striatum after METH, indicating that VMAT2 is a regulator of METH-induced neurodegeneration. The increased METH neurotoxicity in VMAT2 LO occurs in the absence of any significant difference in basal temperature or METH-induced hyperthermia. Furthermore, primary midbrain cultures from VMAT2 LO mice show more oxidative stress generation and a greater loss of TH positive processes than wild-type cultures after METH exposure. Elevated markers of neurotoxicity in VMAT2 LO mice and cultures suggest that the capacity to store DA determines the amount of oxidative stress and neurodegeneration after METH administration.

Guillot, Thomas S.; Shepherd, Kennie R.; Richardson, Jason R.; Wang, Min Z.; Li, Yingjie; Emson, Piers C.; Miller, Gary W.

2014-01-01

135

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.

2005-01-01

136

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

PubMed

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

2009-05-15

137

Glutathione Depletion by L-Buthionine-S,R-Sulfoximine Induces Apoptosis of Cardiomyocytes through Activation of PKC-?.  

PubMed

In the present study, we investigated the effect of intracellular glutathione (GSH) depletion in heart-derived H9c2 cells and its mechanism. L-buthionine-S,R-sulfoximine (BSO) induced the depletion of cellular GSH, and BSO-induced reactive oxygen species (ROS) production was inhibited by glutathione monoethyl ester (GME). Additionally, GME inhibited BSO-induced caspase-3 activation, annexin V-positive cells, and annexin V-negative/propidium iodide (PI)-positive cells. Treatment with rottlerin completely blocked BSO-induced cell death and ROS generation. BSO-induced GSH depletion caused a translocation of PKC-? from the cytosol to the membrane fraction, which was inhibited by treatment with GME. From these results, it is suggested that BSO-induced depletion of cellular GSH causes an activation of PKC-? and, subsequently, generation of ROS, thereby inducing H9c2 cell death. PMID:24244823

Kim, Young-Ae; Kim, Mi-Young; Jung, Yi-Sook

2013-09-30

138

Glutathione Depletion by L-Buthionine-S,R-Sulfoximine Induces Apoptosis of Cardiomyocytes through Activation of PKC-?  

PubMed Central

In the present study, we investigated the effect of intracellular glutathione (GSH) depletion in heart-derived H9c2 cells and its mechanism. L-buthionine-S,R-sulfoximine (BSO) induced the depletion of cellular GSH, and BSO-induced reactive oxygen species (ROS) production was inhibited by glutathione monoethyl ester (GME). Additionally, GME inhibited BSO-induced caspase-3 activation, annexin V-positive cells, and annexin V-negative/propidium iodide (PI)-positive cells. Treatment with rottlerin completely blocked BSO-induced cell death and ROS generation. BSO-induced GSH depletion caused a translocation of PKC-? from the cytosol to the membrane fraction, which was inhibited by treatment with GME. From these results, it is suggested that BSO-induced depletion of cellular GSH causes an activation of PKC-? and, subsequently, generation of ROS, thereby inducing H9c2 cell death.

Kim, Young-Ae; Kim, Mi-Young; Jung, Yi-Sook

2013-01-01

139

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

2005-01-01

140

Orphanin FQ reduces morphine-induced dopamine release in the nucleus accumbens: a microdialysis study in rats  

Microsoft Academic Search

The effects induced by orphanin FQ (OFQ) on morphine-induced dopamine (DA), 3,4-dihydroxyphenilacetic acid (DOPAC) and homovanillic acid (HVA) release in the nucleus accumbens were studied in rats by using microdialysis with electrochemical detection. Morphine administered intraperitoneally (i.p., 2, 5 and 10 mg\\/kg) dose-dependently increased DA and metabolites release in the nucleus accumbens. OFQ intracerebroventricularly (i.c.v.) administered at doses of 2,

Amalia Di Giannuario; Stefano Pieretti; Anna Catalani; A Loizzo

1999-01-01

141

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

1979-01-01

142

Mechanisms of blood pressure increase induced by dopamine in hypotensive preterm neonates  

Microsoft Academic Search

AIMSTo compare changes in global haemodynamics as well as anterior cerebral and superior mesenteric artery perfusion after dopamine treatment.METHODSAnterior cerebal and superior mesenteric artery perfusion was measured using Doppler ultrasonography in hypotensive preterm neonates in whom cardiac output increased (group 1, n=10) or decreased (group 2, n=40) after dopamine treatment.RESULTSDespite a lower dopamine infusion rate, the blood pressure increase (mm

J Zhang; D J Penny; N S Kim; V Y H Yu; J J Smolich

1999-01-01

143

Extent of pre-operative L-DOPA-induced dyskinesia predicts the severity of graft-induced dyskinesia after fetal dopamine cell transplantation.  

PubMed

Graft-induced dyskinesia has emerged as a problematic side effect after transplantation of fetal dopamine cells into the striatum of patients with Parkinson's disease. These adverse effects of dystonic and choreatiform hyperkinesias that persisted even after withdrawal of L-DOPA medication are not yet fully understood, which poses a main obstacle for the re-initiation of neural transplantation in Parkinson's disease. The severity of pre-operative L-DOPA-induced dyskinesia has been proposed as one of several parameters influencing the development of graft-induced dyskinesia. We have therefore characterized graft-induced dyskinesia in the rat model of Parkinson's disease in animals with either mild or severe pre-operative L-DOPA-induced dyskinesia. We show that animals with intrastriatal grafts of fetal dopamine cells and severe pre-operative L-DOPA-induced dyskinesia will reduce their L-DOPA-induced dyskinesia scores by more than 75% but at the same time develop graft-induced dyskinesia of intermediate to strong severity. In contrast, animals with dopamine grafts of similar size but only mild pre-operative L-DOPA-induced dyskinesia also developed graft-induced dyskinesia but this was very mild and of intermediate severity only in a single animal. Severity of pre-operative L-DOPA-induced dyskinesia was correlated with the severity of graft-induced dyskinesia. Our data suggest that patients with no or only mild L-DOPA-induced dyskinesia may carry a lower risk for the development of graft-induced dyskinesia and therefore are better candidates to receive intracerebral grafts of fetal dopamine cells as compared to patients with more pronounced L-DOPA-induced dyskinesia. PMID:21946270

García, Joanna; Carlsson, Thomas; Döbrössy, Máté; Nikkhah, Guido; Winkler, Christian

2011-12-01

144

Role of dopamine D2 receptors in ischemia/reperfusion induced apoptosis of cultured neonatal rat cardiomyocytes  

PubMed Central

Background Myocardial ischemia/reperfusion injury is the major cause of morbidity and mortality for cardiovascular diseases. Dopamine D2 receptors are expressed in cardiac tissues. However, the roles of dopamine D2 receptors in myocardial ischemia/reperfusion injury and cardiomyocyte apoptosis are unclear. Here we investigated the effects of both dopamine D2 receptors agonist (bromocriptine) and antagonist (haloperidol) on apoptosis of cultured neonatal rat ventricular myocytes induced by ischemia/reperfusion injury. Methods Myocardial ischemia/reperfusion injury was simulated by incubating primarily cultured neonatal rat cardiomyocytes in ischemic (hypoxic) buffer solution for 2 h. Thereafter, these cells were incubated for 24 h in normal culture medium. Results Treatment of the cardiomyocytes with 10 ?M bromocriptine significantly decreased lactate dehydrogenase activity, increased superoxide dismutase activity, and decreased malondialdehyde content in the culture medium. Bromocriptine significantly inhibited the release of cytochrome c, accumulation of [Ca2+]i, and apoptosis induced by ischemia/reperfusion injury. Bromocriptine also down-regulated the expression of caspase-3 and -9, Fas and Fas ligand, and up-regulated Bcl-2 expression. In contrast, haloperidol (10 ?M) had no significant effects on the apoptosis of cultured cardiomyocytes under the aforementioned conditions. Conclusions These data suggest that activation of dopamine D2 receptors can inhibit apoptosis of cardiomyocytes encountered during ischemia/reperfusion damage through various pathways.

2011-01-01

145

Greater Ethanol-Induced Locomotor Activation in DBA/2J versus C57BL/6J Mice Is Not Predicted by Presynaptic Striatal Dopamine Dynamics  

PubMed Central

A large body of research has aimed to determine the neurochemical factors driving differential sensitivity to ethanol between individuals in an attempt to find predictors of ethanol abuse vulnerability. Here we find that the locomotor activating effects of ethanol are markedly greater in DBA/2J compared to C57BL/6J mice, although it is unclear as to what neurochemical differences between strains mediate this behavior. Dopamine elevations in the nucleus accumbens and caudate-putamen regulate locomotor behavior for most drugs, including ethanol; thus, we aimed to determine if differences in these regions predict strain differences in ethanol-induced locomotor activity. Previous studies suggest that ethanol interacts with the dopamine transporter, potentially mediating its locomotor activating effects; however, we found that ethanol had no effects on dopamine uptake in either strain. Ex vivo voltammetry allows for the determination of ethanol effects on presynaptic dopamine terminals, independent of drug-induced changes in firing rates of afferent inputs from either dopamine neurons or other neurotransmitter systems. However, differences in striatal dopamine dynamics did not predict the locomotor-activating effects of ethanol, since the inhibitory effects of ethanol on dopamine release were similar between strains. There were differences in presynaptic dopamine function between strains, with faster dopamine clearance in the caudate-putamen of DBA/2J mice; however, it is unclear how this difference relates to locomotor behavior. Because of the role of the dopamine system in reinforcement and reward learning, differences in dopamine signaling between the strains could have implications for addiction-related behaviors that extend beyond ethanol effects in the striatum.

Rose, Jamie H.; Calipari, Erin S.; Mathews, Tiffany A.; Jones, Sara R.

2013-01-01

146

Evidence of Radiation-Induced Dopant Neutralization in Partially-Depleted SOI NMOSFETs  

Microsoft Academic Search

Radiation-induced dopant passivation is evidenced for the first time in partially-depleted SOI n-channel MOSFETs. Isochronal annealing experiments following 10 Mrad(SiO2) irradiation demonstrate that the neutralization of boron atoms in the NMOSFET body is most pronounced in the 125degC-150degC temperature range. This results in an abrupt decrease of the threshold voltage and the subthreshold swing, due to the transition of the

Kerem Akarvardar; Ronald D. Schrimpf; Daniel M. Fleetwood; Sorin Cristoloveanu; Pierre Gentil; Benjamin J. Blalock

2007-01-01

147

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

Microsoft Academic Search

Depleted uranium (DU) is a kind of radioactive heavy metal which can enter into the body via inhalation (aerosols), ingestion\\u000a (drinking and eating) and wounds (embedded), and causes chemical and\\/or radiation-induced toxicities. In this study, male\\u000a Sprague Dawley rats were surgically implanted in gastrocnemius muscle with DU fragments at three dose levels (low-dose, medium-dose\\u000a and high-dose), with biologically inert tantalum

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

2009-01-01

148

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

Microsoft Academic Search

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

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

2004-01-01

149

Transient reduction of human left ventricular mass in carnitine depletion induced by antibiotics containing pivalic acid  

Microsoft Academic Search

OBJECTIVE--To study the effect of induced carnitine depletion on myocardial structure and function. SUBJECTS AND DESIGN--7 healthy adult volunteers given 1200 mg pivmecillinam per day for 7-8 weeks were studied by echocardiography before and after 7-8 weeks of treatment and a 15 months follow up after the treatment period. SETTING--Teaching hospital. MAIN OUTCOME MEASURES--Carnitine concentration in serum, urine, and muscle

K. Abrahamsson; M. Mellander; B. O. Eriksson; E. Holme; U. Jodal; A. Jönsson; S. Lindstedt

1995-01-01

150

Extended Methamphetamine Self-Administration in Rats Results in a Selective Reduction of Dopamine Transporter Levels in the Prefrontal Cortex and Dorsal Striatum Not Accompanied by Marked Monoaminergic Depletion  

PubMed Central

Chronic abuse of methamphetamine leads to cognitive dysfunction and high rates of relapse, paralleled by significant changes of brain dopamine and serotonin neurotransmission. Previously, we found that rats with extended access to methamphetamine self-administration displayed enhanced methamphetamine-primed reinstatement of drug-seeking and cognitive deficits relative to limited access animals. The present study investigated whether extended access to methamphetamine self-administration produced abnormalities in dopamine and serotonin systems in rat forebrain. Rats self-administered methamphetamine (0.02-mg/i.v. infusion) during daily 1-h sessions for 7 to 10 days, followed by either short- (1-h) or long-access (6-h) self-administration for 12 to 14 days. Lever responding was extinguished for 2 weeks before either reinstatement testing or rapid decapitation and tissue dissection. Tissue levels of monoamine transporters and markers of methamphetamine-induced toxicity were analyzed in several forebrain areas. Long-access methamphetamine self-administration resulted in escalation of daily drug intake (?7 mg/kg/day) and enhanced drug-primed reinstatement compared with the short-access group. Furthermore, long-, but not short-access to self-administered methamphetamine resulted in persistent decreases in dopamine transporter (DAT) protein levels in the prefrontal cortex and dorsal striatum. In contrast, only minor alterations in the tissue levels of dopamine or its metabolites were found, and no changes in markers specific for dopamine terminals or glial cell activation were detected. Our findings suggest that persistent methamphetamine seeking is associated with region-selective changes in DAT levels without accompanying monoaminergic neurotoxicity. Greater understanding of the neuroadaptations underlying persistent methamphetamine seeking and cognitive deficits could yield targets suitable for future therapeutic interventions.

Rocha, Angelica; See, Ronald E.; Pacchioni, Alejandra M.; McGinty, Jacqueline F.; Kalivas, Peter W.

2009-01-01

151

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.

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.

2013-01-01

152

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

PubMed

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

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

2014-04-15

153

Ovarian Tumor-Induced T Cell Suppression Is Alleviated by Vascular Leukocyte Depletion1  

PubMed Central

The ovarian cancer microenvironment recruits an array of immune cells to the site of tumor growth. Within the peritoneal ascites of both humans and mice, the predominant population of tumor-infiltrating leukocytes is a CD11c+CD11b+ population variably referred to as vascular leukocytes (VLCs), tumor-associated macrophages, and immature dendritic cells. We have previously shown that these cells are critical for tumor growth because their selective elimination from the peritoneal tumor microenvironment inhibited tumor progression. However, the underlying mechanism by which this therapy was efficacious is poorly understood. Here, we use the murine ID8 ovarian tumor model to demonstrate that the tumor microenvironment induces in vivo immunosuppression of T cells and that the SR-A+ VLCs mediate this suppression. Importantly, the elimination of SR-A+ VLCs from the peritoneum of tumor-bearing mice relieves the T cell suppression. Moreover, the profound changes that VLC elimination has on the immune system are T cell-dependent because the protective antitumor effect of VLC elimination does not occur when CD8 T cells are concomitantly depleted. These results were confirmed and extended with the use of a genetic model for VLC depletion, which demonstrated that short-term therapeutic depletion of VLCs alleviates immunosuppression and allows for efficacious vaccination against model tumor antigens in tumor-bearing mice. These studies provide a mechanistic explanation for how leukocytes contribute to ovarian tumor progression and, correspondingly, how leukocyte depletion inhibits tumor growth.

Bak, S Peter G; Hart, Kevin; Berwin, Brent

2009-01-01

154

Polymyxin B increases the depletion of T regulatory cell induced by purinergic agonist.  

PubMed

Regulatory T cells (Treg) are important in the development of immune tolerance under normal physiological conditions. However, in pathological situations such as cancer, Treg increases have been correlated with bad prognoses. Treg depletion can be achieved in vitro under several stimuli, including the activation of the purinergic P2X7 receptor. Our aim was to determine whether polymyxin B (PMB), which is a positive modulator of this receptor, could affect mice Treg depletion by ATP and related compounds. For that purpose, we evaluated by flow cytometry changes in Treg populations under several treatments with PMB and/or purinergic agonists and antagonists. We found that both ATP and NAD induce a dose-dependent decrease on the Treg CD4+ CD25+ population. PMB not only potentiated the effect of exogenous ATP and NAD, but also decreased the CD4+ CD25+ population when it was applied alone. While ATP mediated effects are related to the P2X7 receptor, PMB effects appear to be related to another mechanism. We conclude that PMB positively modulates the depletion of the CD4+ CD25+ population of Treg. Therefore PMB could constitute a non-canonical drug with potential use on Treg depletion and cancer treatment. PMID:22118797

Cappelli, Claudio; López, Ximena; Labra, Yohana; Montoya, Margarita; Fernández, Ricardo; Imarai, Mónica; Rojas, Juan Luis; Miranda, Dante; Escobar, Alejandro; Acuńa-Castillo, Claudio

2012-03-01

155

Increased cellular activity in rat insular cortex after water and salt ingestion induced by fluid depletion.  

PubMed

Insular cortex (IC) receives inputs from multiple sensory systems, including taste, and from receptors that monitor body electrolyte and fluid balance and blood pressure. This work analyzed metabolic activity of IC cells after water and sodium ingestion induced by sodium depletion. Rats were injected with the diuretic furosemide (10 mg/kg body wt), followed 5 min later by injections of the angiotensin-converting enzyme inhibitor captopril (5 mg/kg body wt). After 90 min, some rats received water and 0.3 M NaCl to drink for 2 h while others did not. A third group had access to water and saline but was not depleted of fluids. All rats were killed for processing of brain tissue for Fos-immunoreactivity (Fos-ir). Nondepleted animals had weak-to-moderate levels of Fos-ir within subregions of IC. Fluid-depleted rats without fluid access had significantly increased Fos-ir in all areas of IC. Levels of Fos-ir were highest in fluid-depleted rats that drank water and sodium. Fos-ir levels were highest in anterior regions of IC and lowest in posterior regions of IC. These results implicate visceral, taste, and/or postingestional factors in the increased metabolic activity of cells in IC. PMID:12505866

Pastuskovas, Cinthia V; Cassell, Martin D; Johnson, Alan Kim; Thunhorst, Robert L

2003-04-01

156

NMDA receptor antagonism potentiates the l-DOPA-induced extracellular dopamine release in the subthalamic nucleus of hemi-parkinson rats.  

PubMed

Long term treatment with L-3,4-dihydroxyphenylalanine (l-DOPA) is associated with several motor complications. Clinical improvement of this treatment is therefore needed. Lesions or high frequency stimulation of the hyperactive subthalamic nucleus (STN) in Parkinson's disease (PD), alleviate the motor symptoms and reduce dyskinesia, either directly and/or by allowing the reduction of the l-DOPA dose. N-methyl-d-aspartate (NMDA) receptor antagonists might have similar actions. However it remains elusive how the neurochemistry changes in the STN after a separate or combined administration of l-DOPA and a NMDA receptor antagonist. By means of in vivo microdialysis, the effect of l-DOPA and/or MK 801, on the extracellular dopamine (DA) and glutamate (GLU) levels was investigated for the first time in the STN of sham and 6-hydroxydopamine-lesioned rats. The l-DOPA-induced DA increase in the STN was significantly higher in DA-depleted rats compared to shams. MK 801 did not influence the l-DOPA-induced DA release in shams. However, MK 801 enhanced the l-DOPA-induced DA release in hemi-parkinson rats. Interestingly, the extracellular STN GLU levels remained unchanged after nigral degeneration. Furthermore, administration of MK 801 alone or combined with l-DOPA did not alter the STN GLU levels in both sham and DA-depleted rats. The present study does not support the hypothesis that DA-ergic degeneration influences the STN GLU levels neither that MK 801 alters the GLU levels in lesioned and non-lesioned rats. However, NMDA receptor antagonists could be used as a beneficial adjuvant treatment for PD by enhancing the therapeutic efficacy of l-DOPA at least in part in the STN. PMID:24863042

El Arfani, Anissa; Bentea, Eduard; Aourz, Najat; Ampe, Ben; De Deurwaerdčre, Philippe; Van Eeckhaut, Ann; Massie, Ann; Sarre, Sophie; Smolders, Ilse; Michotte, Yvette

2014-10-01

157

Depletion of Cellular Glutathione Modulates LIF-Induced JAK1-STAT3 Signaling in Cardiac Myocytes  

PubMed Central

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

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

2012-01-01

158

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

PubMed

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

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

2012-12-01

159

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.

SHIN, HYE RIM; YOU, BO RA; PARK, WOO HYUN

2013-01-01

160

Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria  

Microsoft Academic Search

Background: Studies in experimental animals have implicated the mesolimbic dopaminergic projections into the ventral striatum in the neural processes underlying behavioral reinforcement and motivated behavior; however, understanding the relationship between subjective emotional experience and ventral striatal dopamine (DA) release has awaited human studies. Using positron emission tomography (PET), we correlated the change in endogenous dopamine concentrations following dextroamphetamine (AMPH) administration

Wayne C. Drevets; Clara Gautier; Julie C. Price; David J. Kupfer; Paul E. Kinahan; Anthony A. Grace; Joseph L. Price; Chester A. Mathis

2001-01-01

161

Subchronic methamphetamine treatment enhances ouabain-induced striatal dopamine efflux in vivo.  

PubMed

The effect of manipulation of the Na+ gradient between the intracellular and extracellular media on striatal dopamine (DA) efflux under steady-state conditions after subchronic methamphetamine (MAP) treatment was investigated. Rats were injected with 4 mg/kg MAP or saline (i.p.), once daily for 14 days. Seven days after the last injection, ouabain (10(-4) M), a selective inhibitor of the Na+,K(+)-ATPase, was infused locally through a semi-permeable probe in the striatum. Ouabain induced a significantly greater (P less than 0.01) increase of the DA concentrations in the striatal perfusate in the subchronic MAP than the control group. The levels of 3,4-dihydroxyphenylacetic acid (DOPAC) (P less than 0.05) and 5-hydroxyindoleacetic acid (5-HIAA) (P less than 0.05) were significantly higher in the subchronic MAP than in the control group. Reserpine pretreatment (5 mg/kg, i.p.) did not affect the enhanced ouabain-induced DA efflux (P less than 0.01) in the subchronic MAP group, and the levels of DOPAC (P less than 0.01), 5-HIAA (P less than 0.01) and HVA (P less than 0.01) were also significantly higher in the subchronic MAP than in the control group. In contrast, alpha-methyl-p-tyrosine (250 mg/kg, i.p.) pretreatment abolished the ouabain-induced efflux of DA, DOPAC and HVA, but not 5-HIAA, in both groups. Specific striatal [3H]ouabain binding and striatal Na+,K(+)-ATPase activity in the subchronic MAP and control groups did not differ significantly. These results suggest that subchronic MAP treatment facilitates the efflux of newly synthesized DA, which is induced by the ouabain-induced decrease of the Na+ gradient between intracellular and extracellular media.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1371707

Kanzaki, A; Akiyama, K; Otsuki, S

1992-01-13

162

Cholesterol depletion inhibits src family kinase-dependent calcium mobilization and apoptosis induced by rituximab crosslinking  

PubMed Central

The monoclonal antibody (mAb) rituximab produces objective clinical responses in patients with B-cell non-Hodgkin's lymphoma and antibody-based autoimmune diseases. Mechanisms mediating B-cell depletion by rituximab are not completely understood and may include direct effects of signalling via the target antigen CD20. Like most but not all CD20 mAbs, rituximab induces a sharp change in the solubility of the CD20 protein in the non-ionic detergent Triton-X-100, reflecting a dramatic increase in the innate affinity of CD20 for membrane raft signalling domains. Apoptosis induced by rituximab hypercrosslinking has been shown to require src family kinases (SFK), which are enriched in rafts. In this report we provide experimental evidence that SFK-dependent apoptotic signals induced by rituximab are raft dependent. Cholesterol depletion prevented the association of hypercrosslinked CD20 with detergent-insoluble rafts, and attenuated both calcium mobilization and apoptosis induced with rituximab. CD20 cocapped with the raft-associated transmembrane adaptor LAB/NTAL after hypercrosslinking with CD20 mAbs, regardless of their ability to induce a change in the affinity of CD20 for rafts. Taken together, the data demonstrate that CD20 hypercrosslinking via rituximab activates SFKs and downstream signalling events by clustering membrane rafts in which antibody-bound CD20 is localized in a high-affinity configuration.

Unruh, Tammy L; Li, Haidong; Mutch, Cathlin M; Shariat, Neda; Grigoriou, Lana; Sanyal, Ratna; Brown, Christopher B; Deans, Julie P

2005-01-01

163

CONTROLLED CORTICAL IMPACT INJURY INFLUENCES METHYLPHENIDATE INDUCED CHANGES IN STRIATAL DOPAMINE NEUROTRANSMISSION  

PubMed Central

Traumatic brain injury (TBI) features deficits often ameliorated by dopamine (DA) agonists. We have previously shown deficits in striatal DA neurotransmission, using fast scan cyclic voltammetry (FSCV), after controlled cortical impact (CCI) injury that are reversed after daily treatment with the DA uptake inhibitor Methylphenidate (MPH). The goal of this study was to determine how a single dose of MPH (5 mg/kg) induces changes in basal DA and metabolite levels and with electrically evoked overflow (EO) DA in the striatum of CCI rats. MPH induced changes in EO DA after a two-week daily pretreatment regime with MPH was also assessed. There were no baseline differences in basal DA or metabolite levels. MPH injection significantly increased basal [DA] output in dialysates for control but not injured rats. Also, MPH injection increased striatal peak EO [DA] to a lesser degree in CCI (176% of baseline) versus control rats (233% of baseline). However, daily pretreatment with MPH resulted in CCI rats having a comparable increase in EO [DA] after MPH injection when compared to controls. The findings further support the concept that daily MPH therapy restores striatal DA neurotransmission after CCI.

Wagner, AK; Sokoloski, JE; Chen, X; Harun, R; Clossin, DP; Khan, AS; Andes-Koback, M; Michael, AC; Dixon, CE

2009-01-01

164

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

1998-01-01

165

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.

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

2013-01-01

166

The Selective Dopamine D4 Receptor Antagonist, PNU-101387G, Prevents Stress-Induced Cognitive Deficits in Monkeys  

Microsoft Academic Search

Stress exposure impairs the cognitive functioning of the prefrontal cortex (PFC). Previous research has examined the dopamine (DA) D1 receptor mechanisms underlying this response. The current study performed a preliminary examination of the role of D4 receptor mechanisms by determining whether the selective D4 receptor antagonist, PNU-101387G, could prevent stress-induced working memory deficits in monkeys. Animals were tested on the

Amy F. T. Arnsten; Beth Murphy; Kalpana Merchant

2000-01-01

167

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

1996-01-01

168

Lineweaver-burk analysis for the blocking effects of mammalian dopamine receptor antagonists on dopamine-induced currents in Achatina giant neurones  

Microsoft Academic Search

1.1. We had demonstrated (Emaduddin et al., 1995) the blocking effects of the three mammalian dopamine receptor antagonists, (±)-SKF83566 (mammalian dopamine D1-like receptor antagonist), (+)-UH232 (D2 and D3-like receptor antagonist) and (±)-sulpiride (D2-like receptor antagonist) on the dose (pressure duration)-response curves of dopamine in the three giant neurone types, LVMN (left visceral multiple spike neurone), d-RPeAN (dorsal-right pedal anterior neurone)

Muhammad Emaduddin; Hiroshi Takeuchi

1996-01-01

169

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

1996-01-01

170

The role of de novo catecholamine synthesis in mediating methylmercury-induced vesicular dopamine release from rat pheochromocytoma (PC12) cells.  

PubMed

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

Tiernan, Chelsea T; Edwin, Ethan A; Goudreau, John L; Atchison, William D; Lookingland, Keith J

2013-05-01

171

Mitotic catastrophe and cell death induced by depletion of centrosomal proteins.  

PubMed

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

2013-01-01

172

Receptors involved in the positive inotropic action induced by dopamine on the ventricle of a 7-day-old chick embryo heart.  

PubMed

Earlier experiments only revealed involvement of sympathetic pre-synaptic dopaminergic receptors in dopamine induced inotropism in myocardium. We therefore used electrically stimulated (1 Hz) isolated 7-day-old chick embryo heart ventricles, thought to be devoid of functional sympathetic nerves, to re-investigate post-synaptic receptors involvement and particularly that of dopaminergic receptors in the positive inotropic effect of dopamine. The results showed that noradrenaline, isoprenaline and dopamine produced a positive inotropic effect with a similar efficacy and with an order of potency as follows: Isoprenaline = Noradrenaline > Dopamine. Tyramine induced no significant modification of the "initial tension" indicating that functional sympathetic innervation and/or releasable endogenous catecholamines were not demonstrable in the 7-day-old chick embryo heart ventricle. Propranolol (1 microM) competitively antagonized the positive inotropic response to isoprenaline, noradrenaline and dopamine, meanwhile phentolamine (3 microM) failed to significantly modify the effects of both noradrenaline and dopamine, indicating that these catecholamines induced their positive inotropic effects via stimulation of beta-adrenoceptors; involvement of alpha-adrenergic receptors stimulation was not demonstrable in these effects. Moreover, haloperidol (2 microM) antagonized the positive inotropic response to dopamine but had not any significant effect on the response to isoprenaline. The combined application of both propranolol and haloperidol antagonized the positive inotropic response to dopamine to a greater extent than when these two antagonists were given alone. Consequently, post-synaptic dopaminergic receptors were also involved in the positive inotropic effect of dopamine. Furthermore, in preparations in which sodium channels were inactivated by high potassium physiological salt solution, high concentrations of dopamine (0.1 mM to 1 mM) induced a slow developing electrical and positive inotropic responses which were also inhibited by propranolol and haloperidol, but not by phentolamine. These latter results indicated that like beta-adrenergic stimulation, the slow inward calcium current activated by stimulation of adenylate cyclase, was at least in part involved in the positive inotropic response to dopamine. In conclusion, dopamine induced its positive inotropism via stimulation of post-synaptic beta-adrenergic and dopaminergic receptors. The contribution of dopaminergic receptors in this positive inotropic effect might be of the DA-2 receptors since haloperidol used had been reported to be more DA-2 than DA-1 antagonist. These DA-2 receptors subtypes would mediate activation of adenylate cyclase. PMID:9565766

Ouedraogo, L; Magnon, M; Sawadogo, L; Tricoche, R

1998-01-01

173

Dopamine depletion increases the power and coherence of beta-oscillations in the cerebral cortex and subthalamic nucleus of the awake rat.  

PubMed

Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) of untreated patients implanted with stimulation electrodes for the treatment of Parkinson's disease (PD) demonstrate strong coherence with the cortical electroencephalogram over the beta-frequency range (15-30 Hz). However, studies in animal models of PD emphasize increased temporal coupling in cortico-basal ganglia circuits at substantially lower frequencies, undermining the potential usefulness of these models. Here we show that 6-hydroxydopamine (6-OHDA) lesions of midbrain dopamine neurons are associated with significant increases in the power and coherence of beta-frequency oscillatory activity present in LFPs recorded from frontal cortex and STN of awake rats, as compared with the healthy animal. Thus, the pattern of synchronization between population activity in the STN and cortex in the 6-OHDA-lesioned rodent model of PD closely parallels that seen in the parkinsonian human. The peak frequency of coherent activity in the beta-frequency range was increased in lesioned animals during periods of spontaneous and sustained movement. Furthermore, administration of the dopamine receptor agonist apomorphine to lesioned animals suppressed beta-frequency oscillations, and increased coherent activity at higher frequencies in the cortex and STN, before producing the rotational behaviour indicative of successful lesion. Taken together, these results support a crucial role for dopamine in the modulation of population activity in cortico-basal ganglia circuits, whereby dopaminergic mechanisms effectively filter out synchronized, rhythmic activity at beta-frequencies at the systems level, and shift temporal couplings in these circuits to higher frequencies. These changes may be important in regulating movement. PMID:15813951

Sharott, Andrew; Magill, Peter J; Harnack, Daniel; Kupsch, Andreas; Meissner, Wassilios; Brown, Peter

2005-03-01

174

The dopamine-induced coronary vasoconstrictor response is potentiated by adenosine administration in the dog heart.  

PubMed

The ineffectiveness of beta-adrenergic blockade in abolishing adenosine-induced coronary vasodilation was utilized to demonstrate that dopamine (DA) is capable of eliciting very strong coronary vasoconstrictor actions in vivo. In 2 separate groups of dogs anesthetized with pentobarbital, responses to DA were assessed either by flowmeter recordings or by computer-aided infrared thermography, which senses coronary blood flow-dependent heat emission from the epicardium. In untreated controls, submaximal DA infusions (16 micrograms.kg-1.min-1 iv) elicited a coronary vasodilator response. The thermographic equivalent of this hemodynamic action was an increased epicardial temperature. Pretreatment with oxprenolol (0.5 mg.kg-1 iv) preserved both basic heart activity and cardiac heat emission at levels which were comparable to the control state, but prevented DA mediated excitation of cardiac and coronary beta-adrenoceptors. In this state, DA infusion constricted the coronary arteries and tended to decrease heart emission. However, both types of effects were moderate, and only the hemodynamic effect was statistically significant. If DA was given after the coronary bed had been dilated submaximally by adenosine (30 micrograms.kg-1.min-1 infused into the left heart), the flow-reducing effect of DA became a dramatic phenomenon, and the DA-induced epicardial cooling was significantly potentiated. The results show that after eliminating conventional beta-effects, DA affects the coronary arteries through vasoconstrictor mechanisms. This finding suggests that the DA-induced constriction is limited in undilated coronary arteries by the metabolic autoregulatory capacity of the vessels. PMID:2614933

Kollár, A; Kékesi, V; Juhász-Nagy, A

1989-09-01

175

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.

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

2009-01-01

176

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

PubMed

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

Planeta, C S; DeLucia, R

1998-04-01

177

Role of calcium and cyclophilin D in the regulation of mitochondrial permeabilization induced by glutathione depletion.  

PubMed

The mitochondrial permeability transition (MPT) is a calcium and oxidative stress sensitive transition in the permeability of the mitochondrial inner membrane that plays a crucial role in cell death. However, the mechanism regulating the MPT remains controversial. To study the role of oxidative stress in the regulation of the MPT, we used diethyl maleate (DEM) to deplete glutathione (GSH) in human leukemic CEM cells. GSH depletion increased mitochondrial calcium and reactive oxygen species (ROS) levels in a co-dependent manner causing loss of mitochondrial membrane potential (deltapsi(m)) and cell death. These events were inhibited by the calcium chelator BAPTA-AM and the antioxidants N-acetylcysteine (NAC) and the triphenyl phosphonium-linked ubiquinone derivative MitoQ. In contrast, the MPT inhibitor cyclosporine A (CsA) and small interference RNA (siRNA) knockdown of cyclophilin D (Cyp-D) were not protective. These results indicate that mitochondrial permeabilization induced by GSH depletion is not regulated by the classical MPT. PMID:17888874

Lu, C; Armstrong, J S

2007-11-23

178

Sodium depletion induces Fos immunoreactivity in circumventricular organs of the lamina terminalis.  

PubMed

Acute sodium depletion by peritoneal dialysis (PD) induces c-fos expression in the subfornical organ (SFO) and organum vasculosum laminae terminalis (OVLT), in conscious rats. Fos immunoreactive (Fos-ir) neurons detected by immunohistochemistry first appeared in these nuclei 60 min after PD, increased gradually in the next 4 h and remained high for 27 h following PD. Fos-ir cells were distributed throughout the body of SFO, being the core of the posterior sections preferentially activated, whereas Fos-ir neurons occurred around the periphery of OVLT (annular disposition). When rats were allowed to drink sodium salt (1.8% NaCl) 24 h after PD, there was a marked reversion of the c-fos expression in the OVLT and a comparatively smaller effect in the SFO. Intracerebroventricular infusion of hypertonic CSF (170 mM NaCl) from 30 min before and during 4 h after PD, significantly inhibited the c-fos expression in both nuclei. These results demonstrate that an acute body sodium deficit induces c-fos activity in SFO and OVLT neurons, indicating the special role of these structures in sodium balance regulation. They also show that the sodium-depletion-induced production of Fos in neurons of the lamina terminalis can be modulated by central or systemic reposition of sodium. PMID:7648263

Vivas, L; Pastuskovas, C V; Tonelli, L

1995-05-01

179

Inhibition of the differentiation of human myeloid cell lines by redox changes induced through glutathione depletion.  

PubMed Central

We have investigated the effect of redox changes in vivo on the differentiation of two human myeloid cell lines, HL-60 and KG-1. The glutathione-depleting agent diethyl maleate (DEM) prevented the development of differentiated features in response to phorbol esters, including adherence of the cells to plastic surfaces and repression of the myeloperoxidase and CD34 genes. Moreover, DEM abolished phorbol 12-myristate 13-acetate-induced activation of the transcription factors AP-1 and Egr-1, suggesting that inhibition of differentiation may be due, at least in part, to redox modifications of these proteins. Images Figure 1 Figure 2 Figure 3 Figure 4

Esposito, F; Agosti, V; Morrone, G; Morra, F; Cuomo, C; Russo, T; Venuta, S; Cimino, F

1994-01-01

180

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

1997-01-01

181

Dopamine D 2 agonists, bromocriptine and quinpirole, increase MPP + -induced toxicity in PC12 cells  

Microsoft Academic Search

Dopaminergic cell loss in the mesencephalic substantia nigra is the hallmark of Parkinson’s disease and may be associated\\u000a with abnormal oxidative metabolic activity. However, the delicate balance underlying dopamine decline and oxidative stress\\u000a is still a matter of debate. The aim of this study was to analyze the possible modulation of dopamine D2 agonists and antagonists on MPP+ (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium ion)

Keith Chiasson; BenoÎt Daoust; Daniel Levesque; Maria-Grazia Martinoli

2006-01-01

182

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

1998-01-01

183

Adenosine and Dopamine Receptor Interactions in Striatum and Caffeine-induced Behavioral Activation  

Microsoft Academic Search

This review will examine how dopamine, a monoamine neurotransmitter, and adenosine, a neuromodulator, regulate behavioral activation, primarily as refl ected by locomotor activity, in rodents. Complex interactions among 2 major types of adenosine recep- tors (A1AR and A2AAR) and 2 dopamine receptors (D1R and D2R) occur due to physical interactions that alter their ligand-binding properties and subsequent effects on common

Xiaobin Xie; Vickram Ramkumar; Linda A Toth

184

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.

Stansley, Branden J.; Yamamoto, Bryan K.

2013-01-01

185

Chronic intoxication with 3-nitropropionic acid in rats induces the loss of striatal dopamine terminals without affecting nigral cell viability.  

PubMed

3-Nitropropionic acid (3NP) is a succinate dehydrogenase inhibitor allowing the generation of animal models of Huntington's disease. In the present study, we found that a 5-day continuous chronic infusion of 3NP produces loss of [3H]mazindol binding and tyrosine hydroxylase (TH) immunoreactivity in the striatal area of degeneration. This loss of dopamine terminals was not due to a loss of nigral neurons since the expression of TH as well as the number of TH-expressing neurons remained unaltered in the substantia nigra of rats treated by 3NP. This suggests that the 3NP-induced dopamine terminal loss is secondarily related to the striatal degeneration andlor to a direct effect of 3NP on striatal terminals and not to a primary effect on nigral cells. PMID:14700739

Blum, David; Galas, Marie-Christine; Cuvelier, Laetitia; Schiffmann, Serge N

2004-01-16

186

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.

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.

2004-01-01

187

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-naďve mutants showed moderate alterations in gene expression, especially a reduction in basal levels of activity-regulated transcripts such as Arc and Egr2. The behavioral responses to cocaine were elevated in mutant mice. Locomotor activity after acute treatment, psychomotor sensitization after intermittent drug injections and the conditioned locomotion after saline treatment were increased compared to wild-type littermates. Transgenic mice had significantly higher cocaine conditioned place preference, displayed normal extinction of the conditioned preference, but showed an augmented cocaine-seeking response following priming-induced reinstatement. This enhanced cocaine-seeking response was associated with increased levels of activity-regulated transcripts and prodynorphin. The primary reinforcing effects of cocaine were not altered in the mutant mice as they did not differ from wild-type in cocaine self-administration under a fixed ratio schedule at the training dose. Collectively, our data indicate that expression of a dominant-negative CREB variant exclusively in neurons expressing D1R is sufficient to recapitulate the previously reported behavioral phenotypes associated with virally expressed dominant-negative CREB.

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

2014-01-01

188

D1 and D2 dopamine binding site up-regulation and apomorphine-induced stereotypy.  

PubMed

Treatments with drugs to up-regulate specific receptors is a strategy often employed in mechanism of action studies. In this type of experiment, changes in the numbers of receptors and concomitant changes in an animal's sensitivity to the drug have been used as evidence for the participation of the binding site in the behavior. In these studies, to test for the role of D1 and D2 receptors in apomorphine-induced stereotypy (AIS), dopamine binding sites were up-regulated by appropriate pre-treatments and the ability of these pre-treatments to alter AIS was subsequently investigated. In the first experiment, 19 days of pre-treatment with SCH 23390 or haloperidol selectively increased by 35 and 40% the numbers of striatal D1 and D2 binding sites, respectively, without affecting their affinities. However, when challenged with apomorphine, only the animals pre-treated with the D2 antagonist showed behavioral supersensitivity. In the second experiment, reserpine pre-treatment (30 mg/kg IP, 24-hr pre-test) increased the numbers of D1 binding sites by 18%, but did not significantly alter the numbers of striatal D2 binding sites. Behaviorally, these rats were supersensitive to apomorphine's stereotypy-inducing effects; however, they also showed an increased sensitivity to the ability of either haloperidol or SCH 23390 to block AIS. Moreover, this blockade was only attenuated by a D2 (but not a D1) agonist. Collectively, these data suggest that AIS is mediated by both D1 and D2 binding sites, but that D2 binding sites have a more important role. PMID:2893388

Chipkin, R E; McQuade, R D; Iorio, L C

1987-12-01

189

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

PubMed

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

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

2014-01-01

190

DOPAMINE MEDIATES COCAINE-INDUCED CONDITIONED TASTE AVERSIONS AS DEMONSTRATED WITH CROSS-DRUG PREEXPOSURE TO GBR 12909  

PubMed Central

Although cocaine readily induces taste aversions, little is known about the mechanisms underlying this effect. It has been suggested that its inhibitory effects at one of the monoamine transporters may be mediating this suppression. Using the cross-drug preexposure preparation, the present series of studies examined a possible role of dopamine (DA) in this effect. Male Sprague-Dawley rats were exposed to cocaine (18 mg/kg; Experiment 1) or the selective DA transporter (DAT) inhibitor GBR 12909 (50 mg/kg; Experiment 2) prior to the pairing of a novel saccharin solution with injections of GBR 12909 (32 mg/kg), cocaine (18 mg/kg) or vehicle in a conditioned taste aversion (CTA) procedure. Preexposure to cocaine attenuated aversions induced by itself but not aversions induced by GBR 12909 (Experiment 1). Conversely, preexposure to GBR 12909 attenuated aversions induced by itself and cocaine (Experiment 2). This asymmetry suggests that cocaine and GBR 12909 induce CTAs via similar, but non-identical, mechanisms. These data are discussed in the context of previous work demonstrating roles for dopamine, norepinephrine and serotonin in cocaine-induced CTAs.

Serafine, Katherine M.; Briscione, Maria A.; Rice, Kenner C.; Riley, Anthony L.

2013-01-01

191

Elevation of Ambient Room Temperature has Differential Effects on MDMA-Induced 5HT and Dopamine Release in Striatum and Nucleus Accumbens of Rats  

Microsoft Academic Search

3,4-Methylenedioxymethamphetamine (MDMA) produces acute dopamine and 5-HT release in rat brain and a hyperthermic response, which is dependent on the ambient room temperature in which the animal is housed. We examined the effect of ambient room temperature (20 and 30°C) on MDMA-induced dopamine and 5-HT efflux in the striatum and shell of nucleus accumbens (NAc) of freely moving rats by

Esther O'Shea; Isabel Escobedo; Laura Orio; Veronica Sanchez; Miguel Navarro; A Richard Green; M Isabel Colado

2005-01-01

192

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

USGS Publications Warehouse

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

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

2007-01-01

193

Gastric mucosal lesions induced by complete dopamine system failure in rats. The effects of dopamine agents, ranitidine, atropine, omeprazole and pentadecapeptide BPC 157.  

PubMed

Up to now, for gastric lesions potentiation or induction, as well as determination of endogenous dopamine significance, dopamine antagonist or dopamine vesicle depletor were given separately. Therefore, without combination studies, the evidence for dopamine significance remains split on either blockade of dopamine post-synaptic receptor or inhibition of dopamine storage, essentially contrasting with endogenous circumstances, where both functions could be simultaneously disturbed. For this purpose, a co-administration of reserpine and haloperidol, a dopamine granule depletor combined with a dopamine antagonist with pronounced ulcerogenic effect, was tested, and the rats were sacrificed 24 h after injurious agent(s) administration. Haloperidol (5 mg x kg(-1) b.w. i.p.), given alone, produced the lesions in all rats. Reserpine (5 mg x kg(-1) b.w. i.p.), given separately, also produced lesions. When these agents were given together, the lesions were apparently larger than in the groups injured with separate administration of either haloperidol or reserpine alone. Along with our previous results, when beneficial agents were co-administered, all dopaminomimetics (bromocriptine 10 mg, apomophine 1 mg, amphetamine 20 mg x kg(-1) i.p.) apparently attenuated the otherwise consistent haloperidol-gastric lesions. Likewise, an apparent inhibition of the reserpine-lesions was noted as well. However, if they were given in rats injured with combination of haloperidol and reserpine, their otherwise prominent beneficial effects were absent. Ranitidine (10 mg), omeprazole (10 mg), atropine (10 mg), pentadecapeptide BPC 157 (Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) (10 microg or 10 ng x kg(-1) i.p.) evidently prevented both haloperidol-gastric lesions and reserpine-gastric lesions. Confronted with potentiated lesions following a combination of haloperidol and reserpine, these agents maintained their beneficial effects, noted in the rats treated with either haloperidol or reserpine alone. The failure of dopaminomimetics could be most likely due to more extensive inhibition of endogenous dopamine system activity, and need for remained endogenous dopamine for their salutary effect, whereas the beneficial activities of ranitidine, omeprazole, atropine, pentadecapeptide BPC 157 following dopamine system inhibition by haloperidol+reserpine suggest their corresponding systems parallel those of dopamine system, and they may function despite extensive inhibition of endogenous dopamine system activity. PMID:10791690

Sikiric, P; Separovic, J; Buljat, G; Anic, T; Stancic-Rokotov, D; Mikus, D; Duplancic, B; Marovic, A; Zoricic, I; Prkacin, I; Lovric-Bencic, M; Aralica, G; Ziger, T; Perovic, D; Jelovac, N; Dodig, G; Rotkvic, I; Mise, S; Seiwerth, S; Turkovic, B; Grabarevic, Z; Petek, M; Rucman, R

2000-01-01

194

Resveratrol depletes mitochondrial DNA and inhibition of autophagy enhances resveratrol-induced caspase activation.  

PubMed

We recently demonstrated that resveratrol induces caspase-dependent apoptosis in multiple cancer cell types. Whether apoptosis is also regulated by other cell death mechanisms such as autophagy is not clearly defined. Here we show that inhibition of autophagy enhanced resveratrol-induced caspase activation and apoptosis. Resveratrol inhibited colony formation and cell proliferation in multiple cancer cell types. Resveratrol treatment induced accumulation of LC3-II, which is a key marker for autophagy. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, increased resveratrol-mediated caspase activation and cell death in breast and colon cancer cells. Inhibition of autophagy by silencing key autophagy regulators such as ATG5 and Beclin-1 enhanced resveratrol-induced caspase activation. Mechanistic analysis revealed that Beclin-1 did not interact with proapoptotic proteins Bax and Bak; however, Beclin-1 was found to interact with p53 in the cytosol and mitochondria upon resveratrol treatment. Importantly, resveratrol depleted ATPase 8 gene, and thus, reduced mitochondrial DNA (mtDNA) content, suggesting that resveratrol induces damage to mtDNA causing accumulation of dysfunctional mitochondria triggering autophagy induction. Together, our findings indicate that induction of autophagy during resveratrol-induced apoptosis is an adaptive response. PMID:23088850

Prabhu, Varun; Srivastava, Pragya; Yadav, Neelu; Amadori, Michael; Schneider, Andrea; Seshadri, Athul; Pitarresi, Jason; Scott, Rachael; Zhang, Honghao; Koochekpour, Shahriar; Gogada, Raghu; Chandra, Dhyan

2013-09-01

195

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.

Simonyan, Kristina; Herscovitch, Peter; Horwitz, Barry

2013-01-01

196

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

SciTech Connect

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

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

1989-09-01

197

Dopamine Release Suppression Dependent on an Increase of Intracellular Ca2+ Contributed to Rotenone-induced Neurotoxicity in PC12 Cells  

PubMed Central

Rotenone is an inhibitor of mitochondrial complex I that produces a model of Parkinson’s disease (PD), in which neurons undergo dopamine release dysfunction and other features. In neurons, exocytosis is one of the processes associated with dopamine release and is dependent on Ca2+ dynamic changes of the cell. In the present study, we have investigated the exocytosis of dopamine and the involvement of Ca2+ in dopamine release in PC12 cells administrated with rotenone. Results demonstrated that rotenone led to an elevation of intracellular Ca2+ through Ca2+ influx by opening of the voltage-gated Ca2+ channel and influenced the soluble N-ethylmaleimide attachment protein receptor (SNARE) proteins expression (including syntaxin, vesicle-associated membrane protein 2 (VAMP2) and synaptosome-associated protein 25 (SNAP-25)); pretreatment with a blocker of L-type voltage-activated Ca2+ channels (nifedipine) decreased the intracellular dopamine levels and ROS formation, increased the cell viability and enhanced the neurite outgrowth and exocytosis of synaptic vesicles. These results indicated that the involvement of intracellular Ca2+ was one of the factors resulting in suppression of dopamine release suppression in PC12 cells intoxicated with rotenone, which was associated with the rotenone-induced dopamine neurotoxicity.

Sai, Yan; Chen, Junfeng; Ye, Feng; Zhao, Yuanpeng; Zou, Zhongmin; Cao, Jia; Dong, Zhaojun

2013-01-01

198

BOLA1 Is an Aerobic Protein That Prevents Mitochondrial Morphology Changes Induced by Glutathione Depletion  

PubMed Central

Abstract Aims: The BolA protein family is widespread among eukaryotes and bacteria. In Escherichia coli, BolA causes a spherical cell shape and is overexpressed during oxidative stress. Here we aim to elucidate the possible role of its human homolog BOLA1 in mitochondrial morphology and thiol redox potential regulation. Results: We show that BOLA1 is a mitochondrial protein that counterbalances the effect of L-buthionine-(S,R)-sulfoximine (BSO)-induced glutathione (GSH) depletion on the mitochondrial thiol redox potential. Furthermore, overexpression of BOLA1 nullifies the effect of BSO and S-nitrosocysteine on mitochondrial morphology. Conversely, knockdown of the BOLA1 gene increases the oxidation of mitochondrial thiol groups. Supporting a role of BOLA1 in controlling the mitochondrial thiol redox potential is that BOLA1 orthologs only occur in aerobic eukaryotes. A measured interaction of BOLA1 with the mitochondrial monothiol glutaredoxin GLRX5 provides hints for potential mechanisms behind BOLA1's effect on mitochondrial redox potential. Nevertheless, we have no direct evidence for a role of GLRX5 in BOLA1's function. Innovation: We implicate a new protein, BOLA1, in the regulation of the mitochondrial thiol redox potential. Conclusion: BOLA1 is an aerobic, mitochondrial protein that prevents mitochondrial morphology aberrations induced by GSH depletion and reduces the associated oxidative shift of the mitochondrial thiol redox potential. Antioxid. Redox Signal. 18, 129–138.

Willems, Peter; Wanschers, Bas F.J.; Esseling, John; Szklarczyk, Radek; Kudla, Urszula; Duarte, Isabel; Forkink, Marleen; Nooteboom, Marco; Swarts, Herman; Gloerich, Jolein; Nijtmans, Leo; Koopman, Werner

2013-01-01

199

A receptor-based model for dopamine-induced fMRI signal  

PubMed Central

This report describes a multi-receptor physiological model of the fMRI temporal response and signal magnitude evoked by drugs that elevate synaptic dopamine in basal ganglia. The model is formulated as a summation of dopamine’s effects at D1-like and D2-like receptor families, which produce functional excitation and inhibition, respectively, as measured by molecular indicators like adenylate cyclase or neuroimaging techniques like fMRI. Functional effects within the model are described in terms of relative changes in receptor occupancies scaled by receptor densities and neuro-vascular coupling constants. Using literature parameters, the model reconciles many discrepant observations and interpretations of pre-clinical data. Additionally, we present data showing that amphetamine stimulation produces fMRI inhibition at low doses and a biphasic response at higher doses in the basal ganglia of non-human primates (NHP), in agreement with model predictions based upon the respective levels of evoked dopamine. Because information about dopamine release is required to inform the fMRI model, we simultaneously acquired PET 11C-raclopride data in several studies to evaluate the relationship between raclopride displacement and assumptions about dopamine release. At high levels of dopamine release, results suggest that refinements of the model will be required to consistently describe the PET and fMRI data. Overall, the remarkable success of the model in describing a wide range of preclinical fMRI data indicate that this approach will be useful for guiding the design and analysis of basic science and clinical investigations and for interpreting the functional consequences of dopaminergic stimulation in normal subjects and in populations with dopaminergic neuroadaptations.

Mandeville, Joseph. B.; Sander, Christin Y. M.; Jenkins, Bruce G.; Hooker, Jacob M.; Catana, Ciprian; Vanduffel, Wim; Alpert, Nathaniel M.; Rosen, Bruce R.; Normandin, Marc D.

2013-01-01

200

Hydroxychalcones induce apoptosis in B16-F10 melanoma cells via GSH and ATP depletion.  

PubMed

Searching for leading compounds of new drugs for cancer therapy, we studied the toxicity of 13 hydroxychalcones never tested before toward melanoma cell line (B16-F10). The compounds were obtained by aldolic condensation between aldehydes and hydroxylated acetophenones, in alkaline conditions. Three of them showed cytotoxicity to the cell line. Two of them induced mitochondrial GSH and ATP depletion and promoted cell death through apoptosis in melanoma cells. One of the compounds induced cell death through necrosis but did not significantly decrease the intracellular mitochondrial GSH and ATP levels in melanoma cells. The results suggest that the predominant factor for the activity is the molecule shape, and secondarily the number of hydroxyl groups. PMID:19211173

Navarini, Andréia Lilian Formento; Chiaradia, Louise Domeneghini; Mascarello, Alessandra; Fritzen, Márcio; Nunes, Ricardo José; Yunes, Rosendo Augusto; Creczynski-Pasa, Tânia Beatriz

2009-04-01

201

p53 induces skin aging by depleting Blimp1+ sebaceous gland cells  

PubMed Central

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

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

2014-01-01

202

The membrane-raft protein Flotillin-1 is essential in dopamine neurons for amphetamine-induced behavior in Drosophila  

PubMed Central

The dopamine transporter (DAT) is the primary molecular target responsible for the rewarding properties of the psychostimulants amphetamine (AMPH) and cocaine. AMPH increases extracellular dopamine (DA) by promoting its nonexocytotic release via DAT-mediated efflux. Previous studies in heterologous cells have shown that phosphorylation of the amino terminus of DAT is required for AMPH-induced DA efflux but not for DA uptake. However, the identity of many of the modulatory proteins and the molecular mechanisms that coordinate efflux and the ensuing behavioral effects remain poorly defined. Here we establish a robust assay for AMPH-induced hyperlocomotion in Drosophila melanogaster larvae. Using a variety of genetic and pharmacological approaches we demonstrate that this behavioral response is dependent on DA and on DAT and its phosphorylation. We also show that methylphenidate (MPH), which competitively inhibits DA uptake but does not induce DAT-mediated DA efflux, also leads to DAT-dependent hyperlocomotion, but this response is independent of DAT phosphorylation. Moreover, we demonstrate that the membrane raft protein Flotillin1 is required for AMPH-induced but not MPH-induced hyperlocomotion. These results are the first evidence of a role for a raft protein in an AMPH-mediated behavior. Thus, using our assay we are able to translate molecular and cellular findings to a behavioral level and to differentiate in vivo the distinct mechanisms of two psychostimulants.

Pizzo, Andrea B.; Karam, Caline S.; Zhang, Yuchao; Yano, Hideaki; Freyberg, Robin J.; Karam, David S.; Freyberg, Zachary; Yamamoto, Ai; McCabe, Brian D.; Javitch, Jonathan A.

2012-01-01

203

The membrane raft protein Flotillin-1 is essential in dopamine neurons for amphetamine-induced behavior in Drosophila.  

PubMed

The dopamine transporter (DAT) is the primary molecular target responsible for the rewarding properties of the psychostimulants amphetamine (AMPH) and cocaine. AMPH increases extracellular dopamine (DA) by promoting its nonexocytotic release via DAT-mediated efflux. Previous studies in heterologous cells have shown that phosphorylation of the amino terminus of DAT is required for AMPH-induced DA efflux but not for DA uptake. However, the identity of many of the modulatory proteins and the molecular mechanisms that coordinate efflux and the ensuing behavioral effects remain poorly defined. Here, we establish a robust assay for AMPH-induced hyperlocomotion in Drosophila melanogaster larvae. Using a variety of genetic and pharmacological approaches, we demonstrate that this behavioral response is dependent on DA and on DAT and its phosphorylation. We also show that methylphenidate (MPH), which competitively inhibits DA uptake but does not induce DAT-mediated DA efflux, also leads to DAT-dependent hyperlocomotion, but this response is independent of DAT phosphorylation. Moreover, we demonstrate that the membrane raft protein Flotillin-1 is required for AMPH-induced, but not MPH-induced, hyperlocomotion. These results are the first evidence of a role for a raft protein in an AMPH-mediated behavior. Thus, using our assay we are able to translate molecular and cellular findings to a behavioral level and to differentiate in vivo the distinct mechanisms of two psychostimulants. PMID:22710269

Pizzo, A B; Karam, C S; Zhang, Y; Yano, H; Freyberg, R J; Karam, D S; Freyberg, Z; Yamamoto, A; McCabe, B D; Javitch, J A

2013-07-01

204

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.

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

2014-01-01

205

Block-copolymer-induced long-range depletion interaction and clustering of silica nanoparticles in aqueous solution  

NASA Astrophysics Data System (ADS)

Small-angle neutron scattering (SANS) has been carried out to examine the block-copolymer-induced depletion interaction of charged silica nanoparticles in aqueous solution. The measurements have been performed on fixed concentrations (1 and 10 wt. %) of anionic Ludox silica nanoparticles having sizes of 8 and 16 nm in the presence of 0.1M NaCl and varying concentration of polyethylene oxide-polypropylene oxide-polyethylene oxide P85 [(EO)26(PO)39(EO)26] block copolymer. The presence of the block copolymer induces an attractive depletion interaction between charge-stabilized nanoparticles. The effective interaction of silica nanoparticles is modeled by a combination of two Yukawa potentials accounting for attractive depletion and repulsive electrostatic forces. The depletion interaction is found to be a long-range attraction whose magnitude and range increase with block-copolymer concentration. The depletion interaction is further enhanced by tuning the self-assembly of the block copolymer through the variation of temperature. The increase of the depletion interaction ultimately leads to clustering of nanoparticles and is confirmed by the presence of a Bragg peak in the SANS data. The positioning of the Bragg peak suggests simple-cubic-type packing of particles within the clusters. The scattering from the clusters in the low-Q region is governed by the Porod scattering, indicating that clusters are quite large (order of microns). The depletion interaction is also found to be strongly dependent on the size of the nanoparticles.

Kumar, Sugam; Lee, M.-J.; Aswal, V. K.; Choi, S.-M.

2013-04-01

206

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

NASA Astrophysics Data System (ADS)

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

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

2011-05-01

207

Dopamine, working memory, and training induced plasticity: implications for developmental research.  

PubMed

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 for improving WM capacity. For example, pharmacological interventions acting on the dopaminergic system, such as methylphenidate, improve WM performance. In addition, behavioral interventions for improving WM performance in the form of intensive computerized training have recently been associated with changes in dopamine receptor density. These two different means of improving WM performance--pharmacological and behavioral--are thus associated with similar biological mechanisms in the brain involving dopaminergic systems. This article reviews some of the evidence for the role of dopamine in WM functioning, in particular concerning the link to WM development and cognitive plasticity. Novel data are presented showing that variation in the dopamine transporter gene (DAT1) influences improvements in WM and fluid intelligence in preschool-age children following cognitive training. Our results emphasize the importance of the role of dopamine in determining cognitive plasticity. PMID:22103304

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

2012-05-01

208

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

PubMed

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, Bjřrnar; Uusi-Oukari, Mikko; Aitta-Aho, Teemu; Korpi, Esa R

2014-02-01

209

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

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.

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

2012-01-01

210

Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia  

PubMed Central

Estrogens are known to cause hyperprolactinemia, most probably by acting on the tuberoinfundibular dopaminergic (TIDA) system of the hypothalamus. Dopamine (DA) produced by TIDA neurons directly inhibits prolactin secretion and, therefore, to stimulate prolactin secretion, estrogens inhibit TIDA neurons to decrease DA production. However, the mechanism by which estrogen produces this effect is not clear. In the present study, we used a paradigm involving chronic exposure to low levels of estradiol-17? (E2) to mimic prolonged exposures to environmental and endogenous estrogens. We hypothesized that chronic exposure to low levels of E2 induces oxidative stress in the arcuate nucleus (AN) of the hypothalamus that contains TIDA neurons and causes nitration of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA. This results in a significant decrease in DA and consequently, hyperprolactinemia. To investigate this, adult, intact female cycling rats were implanted with slow-release E2 pellets (20 ng/day) for 30, 60, or 90 days and were compared with old (16–18 mo old) constant estrous (OCE) rats. Chronic E2 exposure significantly increased the expression of glial fibrillary acidic protein and the concentrations of interleukin-1? (IL-1?) and nitrate in the AN that contains perikarya of TIDA neurons and increased nitration of TH in the median eminence (ME) that contains the terminals. These levels were comparable to those seen in OCE rats. We observed a significant decrease in DA concentrations in the ME and hyperprolactinemia in an exposure-dependent manner similar to that seen in OCE rats. It was concluded that chronic exposure to low levels of E2 evokes oxidative stress in the AN to inhibit TIDA neuronal function, most probably leading to hyperprolactinemia.

Kasturi, Badrinarayanan S.; Shin, Andrew C.; Balasubramanian, Priya; Gilbreath, Ebony T.; Subramanian, Madhan; MohanKumar, Puliyur S.

2011-01-01

211

Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia.  

PubMed

Estrogens are known to cause hyperprolactinemia, most probably by acting on the tuberoinfundibular dopaminergic (TIDA) system of the hypothalamus. Dopamine (DA) produced by TIDA neurons directly inhibits prolactin secretion and, therefore, to stimulate prolactin secretion, estrogens inhibit TIDA neurons to decrease DA production. However, the mechanism by which estrogen produces this effect is not clear. In the present study, we used a paradigm involving chronic exposure to low levels of estradiol-17? (E(2)) to mimic prolonged exposures to environmental and endogenous estrogens. We hypothesized that chronic exposure to low levels of E(2) induces oxidative stress in the arcuate nucleus (AN) of the hypothalamus that contains TIDA neurons and causes nitration of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA. This results in a significant decrease in DA and consequently, hyperprolactinemia. To investigate this, adult, intact female cycling rats were implanted with slow-release E(2) pellets (20 ng/day) for 30, 60, or 90 days and were compared with old (16-18 mo old) constant estrous (OCE) rats. Chronic E(2) exposure significantly increased the expression of glial fibrillary acidic protein and the concentrations of interleukin-1? (IL-1?) and nitrate in the AN that contains perikarya of TIDA neurons and increased nitration of TH in the median eminence (ME) that contains the terminals. These levels were comparable to those seen in OCE rats. We observed a significant decrease in DA concentrations in the ME and hyperprolactinemia in an exposure-dependent manner similar to that seen in OCE rats. It was concluded that chronic exposure to low levels of E(2) evokes oxidative stress in the AN to inhibit TIDA neuronal function, most probably leading to hyperprolactinemia. PMID:21178126

MohanKumar, Sheba M J; Kasturi, Badrinarayanan S; Shin, Andrew C; Balasubramanian, Priya; Gilbreath, Ebony T; Subramanian, Madhan; Mohankumar, Puliyur S

2011-03-01

212

Effect of amphetamine-induced dopamine release on radiotracer binding to D1 and D2 receptors in rat brain striatal slices.  

PubMed

The in vivo binding of positron emission tomography (PET) and single photon emission computer tomography (SPECT) radiotracers to dopamine D2 receptors in the striatum can be influenced by competition with endogenous dopamine. The present study was undertaken to determine if a similar inhibition of radiotracer binding to dopamine receptors could be observed following pharmacologically-evoked dopamine release in rat brain striatal slices. Striatal slices were incubated in a large volume of oxygenated Krebs saline and exposed to amphetamine or methamphetamine to evoke dopamine release within the slice. Amphetamine and methamphetamine, at concentrations up to 30 microM, reduced [3H]raclopride binding in the slices by 77% and 86%, respectively, with 50% inhibition at 1.6 microM amphetamine or 3.0 microM methamphetamine. Neither drug produced a significant effect on binding of [3H]SCH 23390 in the slices. This suggests that dopamine was able to interfere with radiotracer binding to D2 but not D1 receptors. The dopamine uptake blockers, cocaine and methylphenidate, had relatively little effect by themselves on [3H]raclopride binding but, by inhibiting amphetamine-induced dopamine release, significantly reduced inhibition of [3H]raclopride binding by a low (3 microM) amphetamine concentration. At a higher (30 microM) amphetamine concentration the inhibition of [3H]raclopride binding was not antagonized by uptake blockers and data obtained from homogenate binding experiments indicated a direct displacement of [3H]raclopride binding by amphetamine at this concentration. In conclusion the data obtained in the present study demonstrate that the effects of amphetamine on striatal radiotracer accumulation observed in PET and SPECT can also be observed in brain slices in vitro and, at least at low amphetamine concentrations, are mediated by competition with released dopamine. PMID:11111836

Gifford, A N; Park, M H; Kash, T L; Herman, L M; Park, E H; Gatley, S J; Volkow, N D

2000-11-01

213

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

Microsoft Academic Search

We provide an approach to significantly break the diffraction limit in coherent anti-Stokes Raman scattering (CARS) microscopy via an additional probe-beam-induced photon depletion (APIPD). The additional probe beam, whose profile is doughnut shaped and whose wavelength is different from the Gaussian probe beam, depletes the phonons to yield an unwanted anti-Stokes signal within a certain bandwidth at the rim of

Wei Liu; Hanben Niu

2011-01-01

214

Depletion of Brain Histamine Produces Regionally Selective Protection against Thiamine Deficiency-Induced Lesions in the Rat  

Microsoft Academic Search

Breakdown of the blood brain barrier and the subsequent accumulation of free radicals, lactate, and glutamate appear to be the immediate causes of thiamine deficiency (TD)-induced damage to thalamus. The mechanisms triggering these events are unknown but recent evidence suggests an important role of histamine. We therefore studied the effects of histamine depletion on thalamic lesions in the pyrithiamine-induced thiamine

Philip J. Langlais; Robert Carter McRee; Julia A. Nalwalk; Lindsay B. Hough

2002-01-01

215

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

PubMed Central

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

2014-01-01

216

The Role of Dopamine in Reinforcement: Changes in Reinforcement Sensitivity Induced by D1-type, D2-type, and Nonselective Dopamine Receptor Agonists  

PubMed Central

Dose-dependent changes in sensitivity to reinforcement were found when rats were treated with low, moderate, and high doses of the partial dopamine D1-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 D2-type receptor agonist quinpirole. Estimates of bias did not differ significantly across exposure to SKF38393 or quinpirole, but did change significantly at the high dose of apomorphine. Estimates of goodness of fit (r2) did not change significantly during quinpirole exposure. Poor goodness of fit was obtained for the high doses of SKF38393 and apomorphine. Decrements in absolute rates of responding were observed at the high dose of quinpirole and at the moderate and high doses of SKF38393 and apomorphine. Changes in r2 and absolute responding may be due to increases in stereotyped behavior during SKF38393 and apomorphine exposure that, in contrast to quinpirole, were distant from the response lever. The present data provide evidence that sensitivity to reward is affected more strongly by dopamine D1-like receptors rather than D2-like receptors, consistent with evidence from other studies investigating consummatory dopamine behavior and the tonic/phasic dopamine hypothesis.

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

2005-01-01

217

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

SciTech Connect

The relation between loss of glutathione due to metal-induced phytochelatin synthesis and oxidative stress was studied in the roots of copper-sensitive and tolerant Silene cucubalus (L.) Wib., resistant to 1 and 40 micromolar Cu, respectively. The amount of nonprotein sulfhydryl compounds other then glutathione was taken as a measure of phytochelatins. At a supply of 20 micromolar Cu, which is toxic for sensitive plants only, phytochelatin synthesis and loss of total glutathione were observed only in sensitive plants within 6 h of exposure. When the plants were exposed to a range of copper concentrations for 3 d, a marked production of phytochelatins in sensitive plants was already observed at 0.5 micromolar Cu, whereas the production in tolerant plants was negligible at 40 micromolar or lower. The highest production in tolerant plants was only 40% of that in sensitive plants. In both varieties, the synthesis of phytochelatins was coupled to a loss of glutathione. Copper at toxic concentrations caused oxidative stress, as was evidenced by both the accumulation of lipid peroxidation products and a shift in the glutathione redox couple to a more oxidized state. Depletion of glutathione by pretreatment with buthionine sulfoximine significantly increased the oxidative damage by copper. At a comparably low glutathione level, cadmium had no effect on either lipid peroxidation or the glutathione redox couple in buthionine sulfoximine-treated plants. These results indicate that copper may specifically cause oxidative stress by depletion of the antioxidant glutathione due to phytochelatin synthesis.

Ric De Vos, C.H.; Vonk, M.J.; Vooijs, R.; Schat, H. (Free Univ. of Amsterdam, (Netherlands))

1992-03-01

218

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

PubMed Central

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

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

2014-01-01

219

Sanguinarine induces apoptosis in A549 human lung cancer cells primarily via cellular glutathione depletion.  

PubMed

Sanguinarine is a plant-derived benzophenanthridine alkaloid and has been shown to possess anti-tumor activities against various cancer cells. In this study, we investigated whether sanguinarine induces apoptosis in A549 human lung cancer cells. Treatment of A549 cells with sanguinarine induced apoptosis in a dose- and time-dependent manner. Treatment with sanguinarine led to activation of caspases and MAPKs as well as increased MKP-1 expression. Importantly, pretreatment with z-VAD-fmk, a pan caspase inhibitor suppressed the sanguinarine-induced apoptosis in A549 cells. Moreover, pretreatment with NAC, a sulfhydryl group-containing reducing agent strongly suppressed the apoptotic response and caspase activation to sanguinarine. However, the sanguinarine-mediated cytotoxicity in A549 cells was not protected by pharmacological inhibition of MAPKs or MKP-1 siRNA-mediated knockdown of MKP-1. These results collectively suggest that sanguinarine induces apoptosis in A549 cells through cellular glutathione depletion and the subsequent caspase activation. PMID:19135517

Jang, Byeong-Churl; Park, Jong-Gu; Song, Dae-Kyu; Baek, Won-Ki; Yoo, Sun Kyun; Jung, Kyung-Hwan; Park, Gy-Young; Lee, Tae-Yun; Suh, Seong-Il

2009-03-01

220

Burst firing in dopamine neurons induced by N-methyl-D-aspartate: role of electrogenic sodium pump.  

PubMed

Dopamine-containing neurons of the mammalian midbrain are required for normal behavior and movements. In vivo they fire action potentials in bursts, but in vitro they discharge regularly spaced action potentials. Burst firing in vitro has now been shown to be robustly induced by the glutamate agonist N-methyl-D-aspartate (NMDA) although not by the non-NMDA agonists kainate or quisqualate. The hyperpolarization between bursts of action potentials results from electrogenic sodium ion extrusion by a ouabain-sensitive pump. This mechanism of burst generation in mammalian neurons may be important in the pathophysiology of schizophrenia and Parkinson's disease. PMID:1329209

Johnson, S W; Seutin, V; North, R A

1992-10-23

221

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.

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

2011-01-01

222

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

PubMed

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

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

2012-11-21

223

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

PubMed

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 (IC?? ~3.9 ?M) and comparable to the antibacterial macrolide azithromycin (IC?? ~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

Tarran, Robert; 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

2013-06-01

224

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.

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

2013-01-01

225

Modulation of dopamine-induced cAMP production in rat striatal cultures by the calcium ionophore A23187 and by phorbol-12-myristate-13-acetate.  

PubMed

The modulation of cAMP formation by protein kinase C (PKC), activated by phorbol-12-myristate-13-acetate, and by Ca2+ entry, using the ionophore A23187, was investigated in rat striatal neurons grown in primary dissociated cell culture. Phorbol-12-myristate-13-acetate (PMA) potentiated forskolin-induced and dopamine-induced cAMP formation in a concentration-dependent manner. In contrast, the calcium ionophore A23187 inhibited dopamine-induced cAMP formation. When PMA and A23187 were tested simultaneously, the levels of cAMP were not statistically different from those found in the presence of dopamine alone. Furthermore, the decreasing effect of A23187 on cAMP formation was enhanced when PKC was desensitized by pretreating the neurons with 1 microM PMA for 18 h. These data indicate that in striatal neurons Ca2+ entry and PKC activation exert opposing effect on cAMP production. PMID:8164517

Schinelli, S; Paolillo, M; Corona, G L

1994-01-01

226

Glutamine depletion potentiates leucocyte-dependent inflammatory events induced by carrageenan or Clostridium difficile toxin A in rats  

PubMed Central

This research investigated the effect of glutamine (Gln) depletion on leucocyte-dependent inflammatory events. Rats were treated intraperitoneally, 16 hr prior to the peak of every parameter evaluated, with either 0·9% NaCl, methionine-sulphoximine (MSO, an inhibitor of endogenous Gln synthesis, 25 mg/kg) or with MSO + Gln (MSO as above plus Gln 3 g/kg in three doses). MSO-induced Gln depletion increased paw oedema induced both by carrageenan (Cg) and by Clostridium difficile toxin A (TxA) (66·2% and 45·5%, respectively; P < 0·05). In dextran-injected animals, oedema and myeloperoxidase (MPO) activity were not modified by Gln depletion. In Cg-treated paws, Gln depletion increased MPO activity by 44% (P < 0·05), interleukin-1? (IL-1?) and tumour necrosis factor-? (TNF-?) concentrations by 47% and 52%, respectively (P < 0·05), and immunostaining for TNF-? in paw tissue. In TxA-injected paws, Gln depletion increased MPO activity (46%; P < 0·05). Gln depletion increased Cg- and TxA-induced neutrophil migration to subcutaneous air pouches by 56% and 77% (P < 0·05), respectively, but did not affect migration induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP). Gln infusions reversed all the effects of MSO. Leucocyte counts did not differ between groups. Gln depletion potentiates acute inflammation, possibly by increasing neutrophil migration through resident cell activation and production of IL-1? and TNF-?. Gln supplementation reverses these effects and may be useful during inflammatory catabolic stress.

Nascimento, Silvia B; Sousa, Romualdo B; Martins, Marcos Jullian B; Souza Gomes, Antoniella; Souza, Marcellus Henrique L P; Guerrant, Richard L; Cunha, Fernando Q; Ribeiro, Ronaldo A; Brito, Gerly A C

2005-01-01

227

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

2012-01-01

228

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.

Undieh, Ashiwel S.

2010-01-01

229

Methamphetamine-Induced Rapid and Reversible Changes in Dopamine Transporter Function: An In Vitro Model  

Microsoft Academic Search

This laboratory has demonstrated that a single methamphet- amine (METH) injection rapidly and reversibly decreases the activity of the dopamine transporter (DAT), as assessed ex vivo in synaptosomes prepared from treated rats. This decrease does not occur because of residual drug introduced by the original injection or nor is it associated with a change in binding of the DAT ligand

Veronica Sandoval; Evan L. Riddle; Yvette V. Ugarte; Glen R. Hanson; Annette E. Fleckenstein

2001-01-01

230

Disprocynium24 induces a dopamine-independent, eukaliuric diuresis and natriuresis in the anaesthetized rat.  

PubMed

In the anaesthetized rat, intravenous administration of the isocyanine 1,1'-diisopropyl-2,4'-cyanine (disprocynium24) at doses up to 600 microg/kg resulted in marked diuresis and natriuresis without affecting urinary potassium excretion. Fractional sodium excretion was increased over 10-fold indicating a high ceiling-diuretic action. The effects of disprocynium24 on renal function were accompanied by a dose-dependent reduction in heart rate (HR) and mean arterial blood pressure (MAP). Acute administration of 600 microg/kg disprocynium24 decreased MAP by 25% and, in addition, caused a fall in glomerular filtration rate (GFR). Since i) disprocynium24 has been shown to interfere with urinary dopamine excretion (UDAV) and ii) dopamine has been implicated with the regulation of renal sodium excretion, we hypothesized that the effects of disprocynium24 might be mediated by its effects on renal dopamine handling. The following findings, however, argue against this hypothesis. First, administration of disprocynium24 in single doses up to 600 microg/kg caused a diuresis and natriuresis, but did not significantly affect U(DA)V. Second, neither the systemic nor the renal response to disprocynium24 were markedly altered by pretreatment with the dopamine D1- or D2-receptor blockers SCH23390 (10 microg x kg(-1) x min[-1]) or S(-)sulpiride (15 microg x kg(-1) x min[-1]), respectively. PMID:9453472

Mühlbauer, B; Luippold, G; Vallon, V; Spitzenberger, F; Russ, H; Osswald, H; Schömig, E

1997-12-01

231

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

PubMed

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

2014-06-01

232

Effects of acute dopamine precusor depletion on immediate reward selection bias and working memory depend on catechol-O-methyltransferase genotype.  

PubMed

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 years) as adults. Moreover, many studies have included female participants 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 male adults (ages 22-40 years), 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, 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

2013-12-01

233

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

PubMed

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

2013-08-01

234

Apoptotic cell death induced by hydrogen peroxide in NT2 parental and mitochondrial DNA depleted cells.  

PubMed

Oxidative stress has been implicated in several pathologies associated with degenerative processes. Mitochondria are involved in cell death by necrosis or apoptosis due to a large load of Ca2+, the formation of reactive oxygen species (ROS), mitochondrial depolarization and the release of cytochrome c that initiates the caspase cascade. Nevertheless, the role of mitochondria in cell death processes induced by hydrogen peroxide (H2O2) has not been fully established. In this study, we analyzed the cytotoxic effect of H2O2 on rho+ human teratocarcinoma (NT2) cells and on mitochondria-DNA depleted rho0 NT2 cells, lacking functional mitochondria. The cells were exposed to H2O2 for 24 h and cell viability was dose-dependently decreased in both cell lines upon H2O2 exposure, although cell susceptibility was higher in rho0 NT2 cells. Moreover a decrease in mitochondrial membrane potential (Deltapsi(m)), mitochondrial cytochrome c release, caspases activation and DNA fragmentation were largely induced by H2O2 and occurred in both cell lines. Nevertheless, increased cell toxicity in rho0 cells upon H2O2 exposure was accompanied by a higher activation of the effector caspases-3 and -6. The data support that, in general, no differences were observed in cells containing functional (rho+) or non-functional (rho0) mitochondria upon H2O2-induced apoptotic cell death. PMID:15234112

Cardoso, Sandra M; Rego, A Cristina; Penacho, Nuno; Oliveira, Catarina R

2004-10-01

235

Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study.  

PubMed

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 (18)F-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 (18)F-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

2013-01-01

236

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

1996-05-01

237

Glutathione depletion induced by c-Myc downregulation triggers apoptosis on treatment with alkylating agents.  

PubMed

Here we investigate the mechanism(s) involved in the c-Myc-dependent drug response of melanoma cells. By using three M14-derived c-Myc low-expressing clones, we demonstrate that alkylating agents, cisplatin and melphalan, trigger apoptosis in the c-Myc antisense transfectants, but not in the parental line. On the contrary, topoisomerase inhibitors, adriamycin and camptothecin, induce apoptosis to the same extent regardless of c-Myc expression. Because we previously demonstrated that c-Myc downregulation decreases glutathione (GSH) content, we evaluated the role of GSH in the apoptosis induced by the different drugs. In control cells treated with one of the alkylating agents or the others, GSH depletion achieved by L-buthionine-sulfoximine preincubation opens the apoptotic pathway. The apoptosis proceeded through early Bax relocalization, cytochrome c release, and concomitant caspase-9 activation, whereas reactive oxygen species production and alteration of mitochondria membrane potential were late events. That GSH was determining in the c-Myc-dependent drug-induced apoptosis was demonstrated by altering the intracellular GSH content of the c-Myc low-expressing cells up to the level of controls. Indeed, GSH ethyl ester-mediated increase of GSH abrogated apoptosis induced by cisplatin and melphalan by inhibition of Bax/cytochrome c redistribution. The relationship among c-Myc, GSH content, and the response to alkylating agent has been also evaluated in the M14 Myc overexpressing clones as well as in the melanoma JR8 c-Myc antisense transfectants. All together, these results demonstrate that GSH plays a key role in governing c-Myc-dependent drug-induced apoptosis. PMID:15153331

Biroccio, Annamaria; Benassi, Barbara; Fiorentino, Francesco; Zupi, Gabriella

2004-01-01

238

Glutathione Depletion Induced by c-Myc Downregulation Triggers Apoptosis on Treatment with Alkylating Agents1  

PubMed Central

Abstract Here we investigate the mechanism(s) involved in the c-Myc-dependent drug response of melanoma cells. By using three M14-derived c-Myc low-expressing clones, we demonstrate that alkylating agents, cisplatin and melphalan, trigger apoptosis in the c-Myc antisense transfectants, but not in the parental line. On the contrary, topoisomerase inhibitors, adriamycin and camptothecin, induce apoptosis to the same extent regardless of c-Myc expression. Because we previously demonstrated that c-Myc downregulation decreases glutathione (GSH) content, we evaluated the role of GSH in the apoptosis induced by the different drugs. In control cells treated with one of the alkylating agents or the others, GSH depletion achieved by l-buthionine-sulfoximine preincubation opens the apoptotic pathway. The apoptosis proceeded through early Bax relocalization, cytochrome c release, and concomitant caspase-9 activation, whereas reactive oxygen species production and alteration of mitochondria membrane potential were late events. That GSH was determining in the c-Myc-dependent drug-induced apoptosis was demonstrated by altering the intracellular GSH content of the c-Myc low-expressing cells up to the level of controls. Indeed, GSH ethyl ester-mediated increase of GSH abrogated apoptosis induced by cisplatin and melphalan by inhibition of Bax/cytochrome c redistribution. The relationship among c-Myc, GSH content, and the response to alkylating agent has been also evaluated in the M14 Myc overexpressing clones as well as in the melanoma JR8 c-Myc antisense transfectants. All together, these results demonstrate that GSH plays a key role in governing c-Myc-dependent drug-induced apoptosis.

Biroccio, Annamaria; Benassi, Barbara; Fiorentino, Francesco; Zupi, Gabriella

2004-01-01

239

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.

1986-04-01

240

Specific oxidative stress profile associated with partial striatal dopaminergic depletion by 6-hydroxydopamine as assessed by a novel multifunctional marker molecule.  

PubMed

Real time oxidative stress in the extracellular compartment of rat striatum was characterized by microdialysis with synthetic non-dialyzable marker molecules composed of linoleic acid, tyrosine and guanosine (N-linoleoyl tyrosine (LT) and N-linoleoyl tyrosine 2'-deoxyguanosyl ester (LTG)). Partial dopaminergic deafferentation was induced by injection of 6-hydroxydopamine (250 microg) to the left lateral ventricle, which depleted ipsilateral striatal dopamine by 46% and dopaminergic cells in left substantia nigra by 44%, 5 weeks after administration. Resting microdialysate dopamine levels in dopamine-depleted striatum were not different from sham-operated rats, although the ratio of oxidized metabolites of dopamine to free dopamine was significantly increased. Hydroperoxide and epoxy products of the linoleoyl portion of LT and LTG were detected in the striatal microdialysate by LC/MS/MS following initial separation by HPLC and were significantly increased in dopamine-depleted compared with control striatum without an increase in guanosine or tyrosine oxidation or nitration. Systemic administration of N-acetyl cysteine (350 mg/kg i.p.) decreased the increment in hydroperoxide and epoxy metabolites to levels not significantly different from control. Oxidation activity towards polyunsaturated fatty acids is present in the extracellular space of partially dopamine-denervated striatum, whereas oxidized glutathione and oxysterol levels in striatal tissue are decreased, possibly indicative of a compensatory response. PMID:20370558

Aluf, Y; Vaya, J; Khatib, S; Loboda, Y; Kizhner, S; Finberg, John P M

2010-06-01

241

Induced PDK1 kinase activity suppresses apoptosis in intestinal epithelial cells by activating Akt signaling following polyamine depletion  

PubMed Central

Apoptosis plays a critical role in the maintenance of gut mucosal homeostasis and is highly regulated by numerous factors including polyamines. Decreasing cellular polyamines promotes the resistance of intestinal epithelial cells (IECs) to apoptosis by increasing Akt kinase activity, but the exact mechanisms by which polyamine depletion activates Akt remain unknown. 3-phosphoinositide-dependent protein kinase-1 (PDK1), functions as a downstream of phosphatidylinositol-3 kinase (PI3K) and upstream of Akt and serves as a major regulator of Akt activity. The current study determined if polyamines regulate Akt activity by altering PDK1. Studies were conducted in IEC-6 cells, derived from rat small intestinal crypts. Depletion of cellular polyamines induced PDK1 phosphorylation and increased its kinase activity, which were prevented by exogenous polyamine putrescine. Induced PDK1 activation following polyamine depletion was associated with an increase in phosphorylated Akt (pAkt) and Akt kinase activity. In contrast, polyamine depletion did not alter levels of total PDK1 and Akt proteins. PDK1 silencing in polyamine-deficient cells not only prevented the induced Akt activation but also blocked the increased resistance to apoptosis. These results indicate that polyamine depletion enhanced Akt phosphorylation by increasing PDK1 kinase activity, thereby protecting IECs against apoptosis.

Keledjian, Kaspar M; Marasa, Bernard S; Wang, Jian-Ying; Rao, Jaladanki N

2012-01-01

242

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

PubMed

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. © 2012 Wiley Periodicals, Inc. Environ Toxicol 29: 867-875, 2014. PMID:22996800

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

2014-08-01

243

Amantadine protects dopamine neurons by a dual action: reducing activation of microglia and inducing expression of GNDF in astroglia  

PubMed Central

Amantadine is commonly given to alleviate L-DOPA-induced dyskinesia of Parkinson’s disease (PD) patients. Animal and human evidence showed that amantadine may also exert neuroprotection in several neurological disorders. Additionally, it is generally believed that this neuroprotection results from the ability of amantadine to inhibit glutamatergic NMDA receptor. However, several lines of evidence questioned the neuroprotection capacity of NMDA receptor antagonists in animal models of PD. Thus the cellular and molecular mechanism of neuroprotection of amantadine remains unclear. Using primary cultures with different composition of neurons, microglia, and astroglia we investigated the direct role of these different glial cell types in the neuroprotective effect of amantadine. First, amantadine protected rat midbrain cultures from either MPP+ or lipopolysaccharide (LPS), two toxins commonly used PD models. Second, our studies revealed that amantadine reduced both LPS- and MPP+ -induced toxicity of dopamine neuron through 1) the inhibition of the release of microglial pro-inflammatory factors, 2) an increase in expression of neurotrophic factor such as GDNF from astroglia. Lastly, differently from the general view on amantadine´s action, we provided evidence suggesting that NMDA receptor inhibition was not crucial for the neuroprotective effect of amantadine. In conclusion, we report that amantadine protected dopamine neurons in two PD models through a novel dual mechanism, namely reducing the release of pro-inflammatory factors from activated microglia and increasing the expression of GNDF in astroglia.

Ossola, Bernardino; Schendzielorz, Nadia; Chen, Shih-Heng; Bird, Gary S.; Tuominen, Raimo K.; Mannisto, Pekka T.; Hong, Jau-Shyong

2011-01-01

244

Tolerance to morphine-induced calcium depletion in regional brain areas: characterization with reserpine and protein synthesis inhibitors.  

PubMed Central

1 Administration of a single dose of morphine sulphate (25 mg/kg) induces tolerance to calcium depletion lasting seven days. 2 There are no apparent changes in calcium content in any of eight discrete brain regions throughout this seven day period. 3 Pretreatment with reserpine (5 mg/kg) did not alter the ability of morphine to induce tolerance. Reserpine alone produced no tolerance to its own calcium depleting action. 4 Cycloheximide (500 mug/kg) but not chloramphenicol (200 mg/kg) effectively prevented development of tolerance. 5 It is concluded that the induction of tolerance to calcium depletion seen after morphine may involve changes in various proteins in membranes of synaptic origin.

Ross, D H

1975-01-01

245

Dopamine and binge eating behaviors  

PubMed Central

Central dopaminergic mechanisms are involved in the motivational aspects of eating and food choices. This review focuses on human and animal data examining the importance of dopamine on binge eating behaviors. Early works examining dopamine metabolites in the cerebrospinal fluid and plasma of bulimic individuals suggested decreased dopamine turnover during the active phase of the illness. While neuroimaging studies of dopamine mechanisms in bulimia nervosa (BN) and binge eating disorder (BED) are limited, genetic studies in humans have implicated an increased frequency of dopamine transporter and associated D2 receptor polymorphisms with binge pathology. Recent examinations of rodent models of dietary-induced binge eating (DIBE) have investigated plausible dopamine mechanisms involved in sustaining binge eating behaviors. In DIBE models, highly palatable foods (fats, sugars and their combination), as well as restricted access conditions appear to promote ingestive responses and result in sustained dopamine stimulation within the nucleus accumbens. Taken together with studies examining the comorbidity of illicit drug use and eating disorders, the data reviewed here support a role for dopamine in perpetuating the compulsive feeding patterns of BN and BED. As such, we propose that sustained stimulation of the dopamine systems by bingeing promoted by preexisting conditions (e.g., genetic traits, dietary restraint, stress, etc.) results in progressive impairments of dopamine signaling. To disrupt this vicious cycle, novel research-based treatment options aiming at the neural substrates of compulsive eating patterns are necessary.

Bello, Nicholas T.; Hajnal, Andras

2010-01-01

246

Depletion of ERK2 but not ERK1 abrogates oncogenic Ras-induced senescence.  

PubMed

In response to oncogenic activation, cells initially undergo proliferation followed by an irreversible growth arrest called oncogene-induced senescence (OIS), an endogenous defense mechanism against tumorigenesis. Oncogenic activation of ERK1/2 is essential for both the initial phase of cellular proliferation as well as subsequent premature senescence, but little is known about the specific contribution of ERK1 versus 2 to OIS. Here we show that depletion of ERK2 but not ERK1 by shRNA knockdown in MEFs leads to continuous proliferation bypassing senescence even in the presence of oncogenic HRAS(V12). Upon depletion of ERK2, induction of both p19(Arf) and p16(Ink4a) was significantly compromised after oncogenic HRAS(V12) expression, attenuating activation of the key tumor suppressors p53 and pRb. Here we demonstrate that ERK2 but not ERK1 indirectly regulates p19(Arf) and p16(Ink4a) both at the transcriptional and translational level. Oncogenic Ras expression after ERK2 knockdown downregulates Fra-1 and c-Jun, components of the activator protein-1 (AP-1) heterodimer essential for transactivation of p19(Arf). Similarly we show a significant decrease in the activation of p38 MAPK and ETS family members which are involved in the induction of p16(Ink4a). The role of ERK2 in translational regulation is observed by the lack of tuberin (TSC2) and p70 ribosomal S6 kinase 1 (p70S6K1) phosphorylation, components of the mTOR pathway, which enhances p19(Arf) mRNA translation during oncogenic Ras-induced senescence. These observations suggest that ERK2 but not ERK1 contributes to upregulation of p19(Arf) and p16(Ink4a) in a transcription- and translation-dependent manner during oncogenic Ras-induced senescence. Taken together, our data indicate that ERK2 is the key ERK isoform mediating the senescence signaling pathway downstream of oncogenic Ras. PMID:23993963

Shin, Jimin; Yang, Jiwon; Lee, Jang Choon; Baek, Kwan-Hyuck

2013-12-01

247

Parvovirus-Induced Depletion of Cyclin B1 Prevents Mitotic Entry of Infected Cells  

PubMed Central

Parvoviruses halt cell cycle progression following initiation of their replication during S-phase and continue to replicate their genomes for extended periods of time in arrested cells. The parvovirus minute virus of mice (MVM) induces a DNA damage response that is required for viral replication and induction of the S/G2 cell cycle block. However, p21 and Chk1, major effectors typically associated with S-phase and G2-phase cell cycle arrest in response to diverse DNA damage stimuli, are either down-regulated, or inactivated, respectively, during MVM infection. This suggested that parvoviruses can modulate cell cycle progression by another mechanism. In this work we show that the MVM-induced, p21- and Chk1-independent, cell cycle block proceeds via a two-step process unlike that seen in response to other DNA-damaging agents or virus infections. MVM infection induced Chk2 activation early in infection which led to a transient S-phase block associated with proteasome-mediated CDC25A degradation. This step was necessary for efficient viral replication; however, Chk2 activation and CDC25A loss were not sufficient to keep infected cells in the sustained G2-arrested state which characterizes this infection. Rather, although the phosphorylation of CDK1 that normally inhibits entry into mitosis was lost, the MVM induced DDR resulted first in a targeted mis-localization and then significant depletion of cyclin B1, thus directly inhibiting cyclin B1-CDK1 complex function and preventing mitotic entry. MVM infection thus uses a novel strategy to ensure a pseudo S-phase, pre-mitotic, nuclear environment for sustained viral replication.

Adeyemi, Richard O.; Pintel, David J.

2014-01-01

248

Trpc2 Depletion Protects RBC from Oxidative Stress-Induced Hemolysis  

PubMed Central

Transient receptor potential channels Trpc2 and Trpc3 are expressed on normal murine erythroid precursors, and erythropoietin stimulates an increase in intracellular calcium ([Ca2+]i) through TRPC2 and TRPC3. Because modulation of [Ca2+]i is an important signaling pathway in erythroid proliferation and differentiation, Trpc2, Trpc3, and Trpc2/Trpc3 double knockout mice were utilized to explore the roles of these channels in erythropoiesis. Trpc2, Trpc3, and Trpc2/Trpc3 double knockout mice were not anemic, and had similar red blood cell counts, hemoglobins, and reticulocyte counts as wild type littermate controls. Although the erythropoietin induced increase in [Ca2+]i was reduced, these knockout mice showed no defects in red cell production. The major phenotypic difference at steady state was that the mean corpuscular volume, mean corpuscular hemoglobin, and hematocrit of red cells were significantly greater in Trpc2 and Trpc2/Trpc3 double knockout mice, and mean corpuscular hemoglobin concentration was significantly reduced. All hematological parameters in Trpc3 knockout mice were similar to controls. When exposed to phenyhydrazine, unlike the Trpc3 knockouts, Trpc2 and Trpc2/Trpc3 double knockout mice showed significant resistance to hemolysis. This was associated with significant reduction in hydrogen peroxide-induced calcium influx in erythroblasts. While erythropoietin induced calcium influx through TRPC2 or TRPC3 is not critical for erythroid production, these data demonstrate that TRPC2 plays an important role in oxidative stress-induced hemolysis which may be related to reduced calcium entry in red cells in the presence of Trpc2 depletion.

Hirschler-Laszkiewicz, Iwona; Zhang, Wenyi; Keefer, Kerry; Conrad, Kathleen; Tong, Qin; Chen, Shu-jen; Bronson, Sarah; Cheung, Joseph Y.; Miller, Barbara A.

2011-01-01

249

The Dopamine Metabolite 3-Methoxytyramine Is a Neuromodulator  

PubMed Central

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

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

2010-01-01

250

The dopamine metabolite 3-methoxytyramine is a neuromodulator.  

PubMed

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

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

2010-01-01

251

Tryptophan depletion and the kinase GCN2 mediate IFN-?-induced autophagy.  

PubMed

IFN-? is a master regulator of the immune responses that occur in the transplanted kidney, acting both on the immune system and on the graft itself. The cellular responses to IFN-? are complex, and emerging evidence suggests that IFN-? may regulate autophagic functions. Conversely, autophagy modulates innate and adaptive immune functions in various contexts. In this study, we identify a novel mechanism by which IFN-? activates autophagy in human kidney epithelial cells and provide new insights into how autophagy regulates immune functions in response to IFN-?. Our results indicate that IFN-? promotes tryptophan depletion, activates the eIF2? kinase general control nonderepressible-2 (GCN2), and leads to an increase in the autophagic flux. Further, tryptophan supplementation and RNA interference directed against GCN2 inhibited IFN-?-induced autophagy. This process is of functional relevance because autophagy regulates the secretion of inflammatory cytokines and growth factors by human kidney epithelial cells in response to IFN-?. These findings assign to IFN-? a novel function in the regulation of autophagy, which, in turn, modulates IFN-?-induced secretion of inflammatory cytokines. PMID:22896630

Fougeray, Sophie; Mami, Iadh; Bertho, Gildas; Beaune, Philippe; Thervet, Eric; Pallet, Nicolas

2012-09-15

252

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

PubMed

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

2013-10-01

253

Depletion of complement does not impact initiation of xenobiotic-induced autoimmune disease  

PubMed Central

Deficiency in Daf1, a complement regulatory protein, has been shown to exacerbate development of various autoimmune diseases and recent studies have suggested that this may be explained by Daf1 acting to limit T-cell hyper-responsiveness. It has been suggested that the absence of Daf1 aggravates autoimmune disease in a complement-dependent manner, but others have shown that activation of T cells in the absence of Daf1 can be complement independent. However, the relationship between Daf1, complement components, lymphocyte activation, cytokine expression and antibody production remains to be determined in mice that are not Daf1 deficient. We have recently demonstrated, in murine mercury-induced autoimmunity (mHgIA), that an accumulation of CD44high Daflow CD4+ T cells is associated with the development of autoimmunity. In this study we observed that complement depletion does not affect the accumulation of activated CD4+ T cells, elevation of splenic interleukin-4 expression and autoantibody production in mHgIA. In addition, neither the accumulation of CD44high Daflow CD4+ T cells nor the down-regulation of Daf1 expression on CD4+ T cells was influenced by a lack of complement. In conclusion, these studies show that initiating events in xenobiotic-induced autoimmunity, including lymphocyte activation, cytokine expression and autoantibody production, are not dependent on complement.

Cauvi, David M; Toomey, Christopher B; Pollard, K Michael

2012-01-01

254

mTOR activation induces tumor suppressors that inhibit leukemogenesis and deplete hematopoietic stem cells after Pten deletion  

PubMed Central

SUMMARY Pten deficiency depletes hematopoietic stem cells (HSCs) but expands leukemia-initiating cells and the mTOR inhibitor, rapamycin, blocks these effects. Understanding the opposite effects of mTOR activation on HSCs versus leukemia-initiating cells could improve anti-leukemia therapies. We found that the depletion of Pten-deficient HSCs was not caused by oxidative stress and could not be blocked by N-acetyl-cysteine. Instead, Pten deletion induced, and rapamycin attenuated, the expression of p16Ink4a and p53 in HSCs, and p19Arf and p53 in other hematopoietic cells. p53 suppressed leukemogenesis and promoted HSC depletion after Pten deletion. p16Ink4a also promoted HSC depletion but had a limited role suppressing leukemogenesis. p19Arf strongly suppressed leukemogenesis but did not deplete HSCs. Secondary mutations attenuated this tumor suppressor response in some leukemias that arose after Pten deletion. mTOR activation therefore depletes HSCs by a tumor suppressor response that is attenuated by secondary mutations in leukemogenic clones.

Lee, Jae Y.; Nakada, Daisuke; Yilmaz, Omer H.; Tothova, Zuzana; Joseph, Nancy M.; Lim, Megan S.; Gilliland, D. Gary; Morrison, Sean J.

2010-01-01

255

Central l-proline attenuates stress-induced dopamine and serotonin metabolism in the chick forebrain.  

PubMed

Using microdialysis, we investigated the effect of l-proline on monoamine release in the medio-rostral neostriatum/hyperstriatum ventrale (MNH) of freely moving and restricted chicks. A 30 min handling-stress resulted in a significant increase in extracellular homovallinic acid (HVA), a dopamine metabolite, and 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, in the MNH. l-Proline, perfused through the microdialysis probe into the MNH during the stressed condition, significantly attenuated the average dialysate concentration of HVA produced by handling-stress. Handling-stress resulted in a significant increase in 5-HIAA levels in the control group, which were attenuated by profusion with l-proline. l-Proline did not significantly modify basal concentrations of HVA or 5-HIAA in the MNH during control conditions. These results show that perfusion of l-proline modified the turnover/metabolism of dopamine and serotonin in the MNH caused by handling-stress. PMID:19450655

Hamasu, Kousuke; Shigemi, Kazutaka; Kabuki, Yusuke; Tomonaga, Shozo; Denbow, D Michael; Furuse, Mitsuhiro

2009-08-21

256

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.

2013-01-01

257

Effect of morphine and lacosamide on levels of dopamine and 5-HIAA in brain regions of rats with induced hypoglycemia.  

PubMed

The study aimed to determine the effect of morphine and lacosamide on levels of dopamine and 5-HIAA in a hypoglycemic model. Female Wistar rats (n = 30), mean weight of 180 g were treated as follow: Group 1 (control) received 0.9% NaCl, Group II; morphine (10 mg kg(-1)), Group III; lacosamide (10 mg kg(-1)), Group IV; insulin (10 U.I. per rat), Group V; morphine (10 mg kg(-1))+insulin, Group VI; lacosamide (10 mg kg(-1))+ insulin. All administrations were made intraperitoneally every 24 h, for 5 days. Animals were sacrificed after the last dose to measure the levels of glucose in blood; dopamine and 5-HIAA in cortex, hemispheres and cerebellum/medulla oblongata regions. Levels of glucose decreased significantly in animals treated with morphine, lacosamide and all groups that received insulin alone or combined with respect to control group. Levels of Dopamine diminished significantly in cortex and increased significantly in hemispheres of animals that received morphine. In cortex, 5-HIAA increase significantly in the groups treated with morphine, morphine+insulin and lacosamide+insulin, however a significant decrease of the same substance was witnessed in cerebellum and medulla oblongata of animals that received morphine or lacosamide plus insulin. GSH increased significantly in cortex and cerebellum/medulla oblongata of animals treated with morphine and lacosamide alone or combined with insulin. Lipid peroxidation decreased significantly in cortex and cerebellum/medulla oblongata of groups that received lacosamide alone or combined with insulin. These results indicate that hypoglycemia induced changes in cellular regulation while morphine and lacosamide are accompanied by biochemical responses. PMID:24783817

Guzman, D Calderon; Garcia, E Hernandez; Mejia, G Barragan; Olguin, H Juarez; Gonzalez, J A Saldivar; Labra Ruiz, N A

2014-01-15

258

Norepinephrine-induced nerve growth factor depletion causes cardiac sympathetic denervation in severe heart failure.  

PubMed

In severe congestive heart failure (CHF), sympathetic overactivity correlates with the exacerbation of cardiac performance. To test the hypothesis that the cardiac sympathetic nerve density dramatically changes with the acceleration of circulating norepinephrine (NE) concentration, we investigated the temporal association of nerve growth factor (NGF) expression in the heart and cardiac sympathetic nerve density during the development of CHF in the continuous NE-infused rats. The animals were analyzed at 0-, 1-, 3-, 7-, 14-, and 28-day after implantation of osmotic pump at a rate of 0.05 mg/kg/hr. The cardiac performance was temporally facilitated in NE-exposed rats at 3-day in accordance with the sympathetic hyper-innervation induced by the augmentation of NGF mRNA expression in the heart. In NE-treated rats, left ventricular end-diastolic pressure was significantly increased after 7-day and marked left ventricular hypertrophy and systemic fluid retention were observed at 28-day. CHF-induced sympathetic overactivity further increased plasma NE concentration in NE-treated rats and finally reached to 16.1+/-5.6 ng/ml at 28-day (control level was 0.39+/-0.1 ng/ml, p<0.01). In the decompensated CHF rats at 28-day, the NGF mRNA expression was conspicuously reduced concomitant with the obvious nerve fiber loss confirmed by the immunostaining of nerve axonal marker, PGP9.5 and sympathetic neuron marker, tyrosine hydroxylase. This resulted in the attenuated tissue NE contents and the exacerbating cardiac performance. The cardiac sympathetic fiber loss was also confirmed in NE-exposed DBH (dopamine beta-hydroxylase)-Cre/Floxed-EGFP (enhanced green fluorescent protein) mice with severe CHF, in which sympathetic nerve could be traced by EGFP. Our results suggest that the cardiac sympathetic nerve density is strictly regulated by the NGF expression in the heart and long-exposure of high plasma NE concentration caused myocardial NGF reduction, following sympathetic fiber loss in severe CHF animals. PMID:20335077

Kimura, Kensuke; Kanazawa, Hideaki; Ieda, Masaki; Kawaguchi-Manabe, Haruko; Miyake, Yoshiko; Yagi, Takashi; Arai, Takahide; Sano, Motoaki; Fukuda, Keiichi

2010-08-25

259

Electrophysiological and amperometric evidence that modafinil blocks the dopamine uptake transporter to induce behavioral activation.  

PubMed

Although the wake-promoting drug modafinil has been shown to bind quite exclusively to the dopamine transporter (DAT), its action in the brain has been thought to be partially independent from the facilitation of the dopaminergic signals. Here we used electrophysiological and amperometric techniques to investigate the effects of modafinil on the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and on the synaptic overflow of dopamine in the dorsal striatum from the sliced tissue of wild-type and cocaine-insensitive genetically modified mice (DAT-CI). Moreover, we examined the consequences of modafinil administration on the locomotor behavior of wild-type and DAT-CI mice. In in vitro experiments, modafinil inhibited the spontaneous firing discharge of the dopaminergic neurons. More consistently, it potentiated firing inhibition and the membrane responses caused by exogenously applied dopamine on these cells. Furthermore, it augmented the stimulus-evoked outflow of DA in the striatum. Noteworthy, modafinil caused locomotor activation in wild-type mice. On the other hand, neither the electrophysiological nor the behavioral effects of modafinil were detected in DAT-CI animals. These results demonstrate that modafinil potentiates brain dopaminergic signals via DAT inhibition by acting at the same binding site of cocaine. Therefore, this mechanism of action explains most of the pharmacological properties of this compound in the clinical setting. PMID:23933217

Federici, M; Latagliata, E C; Rizzo, F R; Ledonne, A; Gu, H H; Romigi, A; Nisticň, R; Puglisi-Allegra, S; Mercuri, N B

2013-11-12

260

Depletion of Human Stratum Corneum Vitamin E: An Early and Sensitive In Vivo Marker of UV Induced PhotoOxidation  

Microsoft Academic Search

As the outermost barrier of the body, the stratum corneum (SC) is frequently and directly exposed to a pro-oxidative environment, including ultraviolet solar radiation (UVR). Therefore, we hypothesized that the SC is susceptible to UVR induced depletion of vitamin E, the major lipophilic antioxidant. To test this, we investigated (i) the susceptibility of SC tocopherols to solar simulated UVR in

Jens J. Thiele; Maret G. Traber; Lester Packer

1998-01-01

261

Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis.  

PubMed

Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita (DC). Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines. However, the mechanisms remained unclear. Using human U2OS osteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescence as evidenced by proliferative arrest, senescence-associated heterochromatinization and a senescence-associated molecular profile. Senescence can render cells resistant to apoptosis. Conversely, chromatin relaxation can reverse the repressive effects of senescence-associated heterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis was suppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation, including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitized dyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex and plays an important role in telomere homeostasis. Defective telomere maintenance resulting in premature senescence is thought to primarily underlie the pathogenesis of X-linked DC. Since U2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function can also induce cellular senescence via mechanisms independent of telomere shortening. PMID:24690175

Lin, Ping; Mobasher, Maral E; Alawi, Faizan

2014-04-18

262

[The pharmacological differences between kynurenine- and korazol-induced seizures (the participation of GABA-B receptors and dopamine)].  

PubMed

In experiments of male SHR (nonbred) and C57B1/6 mice [correction of rats] bicucullin intensified corasole-induced convulsions but had no effect on kynurenine convulsions, removed the anticonvulsive effect of phenibut against kynurenine and did not affect the anticonvulsive effect of diazepam against corasole. Phenibut and baclofen reduced the anticonvulsive effect of diazepam against corasole and caffeine. Haloperidol increased kynurenine-induced convulsions and had no effect on those caused by corasole. Dopamine removed the effect of haloperidol. Haloperidol and 6-oxydopamine weakened the sedative effect of phenibut. Blockade of GAMAB-receptors and weakening of dopaminergic activity are important in the mechanisms of kynurenine convulsions, and blockage of GABAA-receptors unrelated to it is important in the mechanisms of corasole convulsions. A functional antagonism in anticonvulsive activity may exist between these receptors. Bicucullin may probably have an effect both on GABAA- and GABAB-receptors. PMID:9621167

Lapin, I P

1998-01-01

263

Radiation hardening and radiation-induced chromium depletion effects on intergranular stress corrosion cracking of austenitic stainless steels  

SciTech Connect

Available data on neutron-irradiated materials have been analyzed and correlations developed between fluence, yield strength, grain boundary chromium concentration and cracking susceptibility in high-temperature water environments. Large heat-to-heat differences in critical fluence (0.2 to 2.5 n/cm{sup 2}) for IGSCC are documented.In many cases, this variability is consistent with yield strength differences among irradiated materials. IGSCC correlated better to yield strength than to fluence for most heats suggesting a possible role of the radiation-induced hardening (and microstructure) on cracking. However, isolatedheats reveal a wide range of yield strengths from 450 to 800 MPa necessary to promote IGSCC which cannot be understood by strength effects alone. Grain boundary Cr depletion explain differences in IGSCC susceptibility for irradiated stainless steels. Cr contents versus SCC shows that all materials showing IG cracking have some grain boundary depletion ({ge}2%). Grain boundary Cr concentrations for cracking (below {approximately}16 wt %) are in good agreement with similar SCC tests on unirradiated 304 SS with controlled depletion profiles. Heats that prompt variability in the yield strength correlation, are accounted for bydifferences in their interfacial Cr contents. Certain stainless steels are more resistant to cracking even though they have significant radiation-induced Cr depletion. It is proposed that Cr depletion is required for IASCC, but observed susceptibility is modified by other microchemical and microstructural components.

Bruemmer, S.M.; Simonen, E.P.

1993-03-01

264

Radiation hardening and radiation-induced chromium depletion effects on intergranular stress corrosion cracking of austenitic stainless steels  

SciTech Connect

Available data on neutron-irradiated materials have been analyzed and correlations developed between fluence, yield strength, grain boundary chromium concentration and cracking susceptibility in high-temperature water environments. Large heat-to-heat differences in critical fluence (0.2 to 2.5 n/cm[sup 2]) for IGSCC are documented.In many cases, this variability is consistent with yield strength differences among irradiated materials. IGSCC correlated better to yield strength than to fluence for most heats suggesting a possible role of the radiation-induced hardening (and microstructure) on cracking. However, isolatedheats reveal a wide range of yield strengths from 450 to 800 MPa necessary to promote IGSCC which cannot be understood by strength effects alone. Grain boundary Cr depletion explain differences in IGSCC susceptibility for irradiated stainless steels. Cr contents versus SCC shows that all materials showing IG cracking have some grain boundary depletion ([ge]2%). Grain boundary Cr concentrations for cracking (below [approximately]16 wt %) are in good agreement with similar SCC tests on unirradiated 304 SS with controlled depletion profiles. Heats that prompt variability in the yield strength correlation, are accounted for bydifferences in their interfacial Cr contents. Certain stainless steels are more resistant to cracking even though they have significant radiation-induced Cr depletion. It is proposed that Cr depletion is required for IASCC, but observed susceptibility is modified by other microchemical and microstructural components.

Bruemmer, S.M.; Simonen, E.P.

1993-03-01

265

Taste reactivity analysis of 6-hydroxydopamine-induced aphagia: Implications for arousal and anhedonia hypotheses of dopamine function  

Microsoft Academic Search

The deficits in feeding and drinking that result from 6-hydroxydopamine (6-OHDA) lesions of the mesostriatal dopamine system are often explained using either sensorimotor arousal or anhedonia hypotheses. Sensorimotor arousal hypotheses posit that dopamine systems facilitate the capacity of sensory stimuli to activate any motor output. The anhedonia hypothesis suggests that dopamine systems amplify the hedonic impact of positive reinforcers. Natural

Kent C. Berridge; Isabel L. Venier; Terry E. Robinson

1989-01-01

266

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.

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

2013-01-01

267

Dopamine deficiency in mice.  

PubMed

Dopamine is the principal neurotransmitter that mediates a wide range of brain functions, including locomotion, emotion, learning, and neuroendocrine modulation. To clarify the role of dopamine during postnatal development, it is useful to have mutant mice genetically deleting dopamine. In this paper, we describe the mice lacking expression of tyrosine hydroxylase (TH), the first and rate-limiting enzyme of catecholamine biosynthetic pathway, in the dopaminergic neuronal type. In these mice, TH expression in noradrenergic and adrenergic cells was restored. Lack of TH expression in dopaminergic neurons resulted in a marked reduction of dopamine accumulation. This led to multiple behavioral abnormalities at the juvenile stage, which were characterized by a reduction in spontaneous locomotor activity, blockade of methamphetamine-induced hyperactivity, cataleptic behavior, and defect in active avoidance learning. In contrast, development of pituitary gland as well as production and secretion of the pituitary peptide hormones dependent on hypothalamic dopaminergic control were normally maintained in spite of the reduced dopamine synthesis. Our findings provide genetic evidence that dopamine is essential for controlling spontaneous and voluntary movement and emotional learning during postnatal development through the nigrostriatal and mesocorticolimbic pathways. PMID:10984662

Kobayashi, K; Sano, H

2000-09-01

268

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

Microsoft Academic Search

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

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

1974-01-01

269

Reversal effect of DM-9384 on scopolamine-induced acetylcholine depletion in certain regions of the mouse brain.  

PubMed

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 had no effect on the ACh level in the hippocampus, frontal cortex, amygdala and striatum. Nevertheless, in all brain regions, pretreatment with DM-9384 significantly reduced the depletion of ACh induced by scopolamine (0.5 mg/kg, IP) in a nondose-related bell-shaped manner. By contrast, oxiracetam attenuated the effect of scopolamine in the hippocampus, frontal cortex and striatum but not in the amygdala. Physostigmine (0.2 mg/kg, SC) significantly increased ACh levels and reversed the scopolamine-induced ACh depletion in all brain regions. Unlike physostigmine, tacrine (10 mg/kg, PO) increased ACh levels in the striatum but not in the other regions. Tacrine reversed the effect of scopolamine in the hippocampus, amygdala and striatum, but not in the frontal cortex. In the present study, DM-9384 more effectively inhibited scopolamine-induced depletion of ACh levels than the other agents tested. The results obtained indicate that the protective action of DM-9384 against scopolamine-induced amnesia is due to its ability to reverse the ACh depletion. PMID:1798828

Abe, E

1991-01-01

270

Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex.  

PubMed

The mechanism(s) by which serotonin modulates dopamine release in the medial prefrontal cortex is not known, although studies suggest an involvement of 5-HT2 family receptors. We employed in vivo microdialysis and putatively selective 5-HT2A antagonists (M100907, MDL 11,939, SR46349B) to determine if 5-HT2A receptors are responsible for both drug- and stress-induced DA release in the medial prefrontal cortex. MDL 11,939 and SR46349B receptor-binding studies indicated, for the first time, that only MDL 11,939 had greater selectivity for the 5-HT2A vs the 5-HT2C receptor subtypes similar to M100907, and that both showed low or no affinity for non-5-HT2 receptors. Reverse dialysis with 5-HT2A antagonists had little or no effect on basal dopamine efflux. However, intracortical administration of MDL 11,939 or M100907 attenuated dopamine release induced by systemic administration of the 5-HT2 agonist DOI. Dual-probe microdialysis demonstrated that systemic DOI also increased glutamate concentrations in the ventral tegmental area (VTA). This was blocked by intracortical M100907. Cortical perfusion with M100907, or the atypical antipsychotic drug risperidone, but not the 5-HT2B/C ligand SB 206553, also decreased dopamine release induced physiologically by stress. These results indicate that stimulation of cortical 5-HT2A receptors increases the release of dopamine from the mesocortical system. They suggest that this effect may be mediated by increases in glutamate release from corticotegmental projections to the VTA. Additionally, they indicate that cortical 5-HT2A receptors modulate evoked dopamine release, such as that observed physiologically following mild stress. These findings may have implications for the pharmacological treatment of disorders resulting from or exacerbated by stress. PMID:15999145

Pehek, Elizabeth A; Nocjar, Christine; Roth, Bryan L; Byrd, Tara A; Mabrouk, Omar S

2006-02-01

271

Methamphetamine Induces Striatal Neurokinin-1 Receptor Endocytosis Primarily in Somatostatin/NPY/NOS Interneurons and the Role of Dopamine Receptors in Mice  

PubMed Central

Methamphetamine (METH) is a psychostimulant that induces long-term deficits of dopamine terminal markers and apoptotic cell death in the striatum. Our laboratory demonstrated that pharmacological blockade of the neurokinin-1 receptor attenuated the METH-induced damage to the striatal dopamine terminals and the apoptotic cell death of some striatal neurons. Here we employed histological methods to assess the effect of METH on neurokinin-1 receptor trafficking in the striatum as an indirect index of signaling by the neuropeptide substance P (natural ligand for this receptor). Male mice received a single injection of METH (30 mg/kg, i.p.) and were sacrificed 30 minutes later. Immunohistofluorescence confocal microscopy confirmed that the neurokinin-1 receptor is located on cholinergic and somatostatin interneurons of the striatum. METH induced the trafficking of the neurokinin-1 receptor from the membrane into cytoplasmic endosomes primarily in the somatostatin/NPY/NOS interneurons and this phenomenon was attenuated by antagonists of the dopamine D1 (SCH-23390), D2 (raclopride) or neurokinin-1 (WIN-51,708) receptors. These data demonstrate that METH induces the trafficking of the striatal neurokinin-1 receptors principally in the somatostatin/NPY/NOS interneurons and that this phenomenon is dependent on the activity of dopamine D1 and D2 receptors.

Wang, Jing; Angulo, Jesus A.

2010-01-01

272

Effect of the adenosine A2A receptor antagonist MSX-3 on motivational disruptions of maternal behavior induced by dopamine antagonism in the early postpartum rat  

PubMed Central

Rationale Mesolimbic dopamine (DA), particularly in the nucleus accumbens, importantly regulates activational aspects of maternal responsiveness. DA antagonism and accumbens DA depletions interfere with early postpartum maternal motivation by selectively affecting most forms of active maternal behaviors, while leaving nursing behavior relatively intact. Considerable evidence indicates that there is a functional interaction between DA D2 and adenosine A2A receptors in striatal areas, including the nucleus accumbens. Objective This study was conducted to determine if adenosine A2A receptor antagonism could reverse the effects of DA receptor antagonism on early postpartum maternal behavior. Methods The adenosine A2A receptor antagonist MSX-3 (0.25–2.0 mg/kg, IP) was investigated for its ability to reverse the effects of the DA D2 receptor antagonist haloperidol (0.1 mg/kg, IP) on the maternal behavior of early postpartum female rats. Results Haloperidol severely impaired the expression of active maternal components, including retrieval and grouping the pups at the nest site, pup licking, and nest building. Co-administration of MSX-3 (0.25–2.0 mg/kg, IP) with haloperidol produced a dose-related attenuation of the haloperidol-induced behavioral deficits in early postpartum females. Doses of MSX-3 that effectively reversed the effects of haloperidol (0.5, 1.0 mg/kg), when administered in the absence of haloperidol, did not affect maternal responding or locomotor activity. Conclusions Adenosine and DA systems interact to regulate early postpartum maternal responsiveness. This research may potentially contribute to the development of strategies for treatments of psychiatric disorders during the postpartum period, with particular emphasis in maintaining or restoring the mother–infant relationship.

Farrar, Andrew M.; Hockemeyer, Jorg; Muller, Christa E.; Salamone, John D.; Morrell, Joan I.

2011-01-01

273

West Nile virus neuroinvasion and encephalitis induced by macrophage depletion in mice  

Microsoft Academic Search

Summary The encephalitic West Nile virus and its nonneuroinvasive variant, WN-25, were used to study the effect of macrophage depletion on viral invasion of the central nervous system. The in vivo elimination of macrophages was achieved by use of liposome-encapsulated drug dichloromethylene diphosphonate. Depletion of macrophages had an exacerbating effect on the course of the viral infection, exhibited by higher

D. Ben-Nathan; I. Huitinga; S. Lustig; N. van Rooijen; D. Kobiler

1996-01-01

274

Decreased striatal dopamine release underlies increased expression of long-term synaptic potentiation at corticostriatal synapses 24 hours after 3-nitropropionic acid induced chemical hypoxia  

PubMed Central

The striatum is particularly sensitive to the irreversible inhibitor of succinate dehyrdrogenase 3-nitropropionic acid (3-NP). In the present study we examined early changes in behavior and dopamine and glutamate synaptic physiology created by a single systemic injection of 3-NP in Fischer 344 rats. Hind limb dystonia was seen 2 hours after 3-NP injections and rats performed poorly on balance beam and rota-rod motor tests 24 hours later. Systemic 3-NP increased NMDA receptor-dependent long-term potentiation (LTP) at corticostriatal synapses over the same time period. The 3-NP induced corticostriatal LTP was not due to increased NMDA receptor number or function, since 3-NP did not change MK-801 binding or NMDA/AMPA receptor current ratios. The LTP seen 24 hours after 3-NP was D1 receptor-dependent and reversed by exogenous addition of dopamine or a D2 receptor agonist to brain slices. High performance liquid chromatography and fast scan cyclic voltammetry revealed a decrease in dopamine content and release in rats injected 24 hours earlier with 3-NP, and much like the enhanced LTP, dopamine changes were reversed by 48 hours. Tyrosine hydroxylase expression was not changed and there was no evidence of striatal cell loss at 24–48 hours after 3-NP exposure. Sprague-Dawley rats showed similar physiological responses to systemic 3-NP, albeit with reduced sensitivity. Thus, 3-NP causes significant changes in motor behavior marked by parallel changes in striatal dopamine release and corticostriatal synaptic plasticity.

Akopian, Garnik; Crawford, Cynthia; Beal, M. Flint; Cappelletti, Maurand; Jakowec, Michael W.; Petzinger, Giselle M.; Zheng, Ling; Gheorghe, Stacey L.; Reichel, Carmela M.; Chow, Robert; Walsh, John P

2008-01-01

275

Infantile parkinsonism-dystonia: a dopamine "transportopathy"  

PubMed Central

The dopamine transporter (DAT) retrieves the neurotransmitter dopamine from the synaptic cleft at dopaminergic synapses. Variations in solute carrier family 6A, member 3 (SLC6A3/DAT1), the human gene encoding DAT, have been implicated in attention deficit hyperactivity and bipolar disorders, and DAT is a prominent site of action for drugs such as amphetamines and cocaine. In this issue of the JCI, Kurian et al. report that an autosomal recessive infantile parkinsonism-dystonia is caused by loss-of-function mutations in DAT that impair dopamine reuptake (see the related article beginning on page 1595). Though this might be predicted to result in dopamine excess in the synaptic cleft, it likely also causes depletion of presynaptic dopamine stores and possibly downregulation of postsynaptic dopamine receptor function, resulting in impairments in dopaminergic neurotransmission consistent with the clinical presentation. This is the first report of a genetic alteration in DAT function underlying a parkinsonian disorder.

Blackstone, Craig

2009-01-01

276

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.

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

2011-01-01

277

Renal D3 dopamine receptor stimulation induces natriuresis by endothelin B receptor interactions  

PubMed Central

Dopaminergic and endothelin systems participate in the control blood pressure by regulating sodium transport in the renal proximal tubule. Disruption of either the endothelin B receptor (ETB) or D3 dopamine receptor gene in mice produces hypertension. To examine whether these two receptors interact we studied the Wistar–Kyoto (WKY) and spontaneously hypertensive (SHR) rats by selectively infusing reagents into the right kidney of anesthetized rats. The D3 receptor agonist (PD128907) caused natriuresis in WKY rats which was partially blocked by the ETB receptor antagonist. In contrast, PD128907 blunted sodium excretion in the SHRs. We found using laser confocal microscopy that the ETB receptor was mainly located in the cell membrane in control WKY cells. Treatment with the D3 receptor antagonist caused its internalization into intracellular compartments that contained the D3 receptors. Combined use of D3 and ETB antagonists failed to internalize ETB receptors in cells from WKY rats. In contrast in SHR cells, ETB receptors were found mainly in internal compartments under basal condition and thus were likely prevented from interacting with the agonist-stimulated, membrane-bound D3 receptors. Our studies suggest that D3 receptors physically interact with proximal tubule ETB receptors and that the blunted natriuretic effect of dopamine in SHRs may be explained, in part, by abnormal D3/ETB receptor interactions.

Zeng, Chunyu; Asico, Laureano D.; Yu, Changqing; Villar, Van Anthony M.; Shi, Weibin; Luo, Yingjin; Wang, Zheng; He, Duofen; Liu, Yan; Huang, Lan; Yang, Chengming; Wang, Xukai; Hopfer, Ulrich; Eisner, Gilbert M.; Jose, Pedro A.

2014-01-01

278

Music and methamphetamine: conditioned cue-induced increases in locomotor activity and dopamine release in rats.  

PubMed

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 90 min. 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 drugs 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

2011-03-01

279

Reconciling the role of serotonin in behavioral inhibition and aversion: acute tryptophan depletion abolishes punishment-induced inhibition in humans  

PubMed Central

The neuromodulator serotonin has been implicated in a large number of affective and executive functions, but its precise contribution to motivation remains unclear. One influential hypothesis has implicated serotonin in aversive processing; another has proposed a more general role for serotonin in behavioral inhibition. Since behavioral inhibition is a pre-potent reaction to aversive outcomes, it has been a challenge to reconcile these two accounts. Here, we show that serotonin is critical for punishment-induced inhibition, but not overall motor response inhibition or reporting aversive outcomes. We used acute tryptophan depletion to temporarily lower brain serotonin in healthy human volunteers as they completed a novel task designed to obtain separate measures of motor response inhibition, punishment-induced inhibition, and sensitivity to aversive outcomes. Following a placebo treatment, participants were slower to respond under punishment conditions, compared to reward conditions. Tryptophan depletion abolished this punishment-induced inhibition, without affecting overall motor response inhibition or the ability to adjust response bias in line with punishment contingencies. The magnitude of reduction in punishment-induced inhibition depended on the degree to which tryptophan depletion reduced plasma tryptophan levels. These findings extend and clarify previous research on the role of serotonin in aversive processing and behavioral inhibition, and fit with current theorizing on serotonin's involvement in predicting aversive outcomes.

Crockett, Molly J.; Clark, Luke; Robbins, Trevor W.

2009-01-01

280

L-Stepholidine, a natural dopamine receptor D1 agonist and D2 antagonist, inhibits heroin-induced reinstatement.  

PubMed

L-Stepholidine (l-SPD), an alkaloid extract of the Chinese herb Stephania intermedia, is the first compound known to exhibit mixed dopamine D1 receptor agonist/D2 antagonist properties and is a potential medication for the treatment of opiate addiction. The aim of the present study was to investigate the effects of pretreatment with L-SPD on heroin-seeking behavior induced by heroin priming. Male Sprague-Dawley rats were trained to self-administer heroin (0.05mg/kg per infusion) under a fixed ratio 1 schedule for 12 consecutive days and nose-poke responding was extinguished for 12 days, after which reinstatement of drug seeking was induced by heroin priming. Pretreatment with L-SPD (2.5, 5.0 and 10.0mg/kg, i.p.) inhibited the heroin-induced reinstatement of heroin-seeking behavior. Importantly, L-SPD did not affect locomotion, indicating that the observed effects of L-SPD on reinstatement are not the result of motor impairments. The present data suggested that l-SPD inhibits heroin-induced reinstatement and its potential for the treatment of heroin relapse. PMID:24269875

Ma, Baomiao; Yue, Kai; Chen, Lin; Tian, Xiang; Ru, Qin; Gan, Yongping; Wang, Daisong; Jin, Guozhang; Li, Chaoying

2014-01-24

281

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

PubMed

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

2014-04-01

282

Mechanisms of anti-inflammatory property of conserved dopamine neurotrophic factor: inhibition of JNK signaling in lipopolysaccharide-induced microglia.  

PubMed

Microglia are important resident immune cells in the central nervous system (CNS) and involved in the neuroinflammation caused by CNS disorders, including brain trauma, ischemia, stroke, infections, inflammation, and neurodegenerative diseases. Our study explores the hypothesis that conserved dopamine neurotrophic factor (CDNF), a secretory neurotrophic factor, may provide a novel therapy for associated with neuroinflammation related to the microglia. We observed that CDNF was upregulated in rat primary microglia treated with 1 ?g/mL lipopolysaccharide, an inflammatory inducer, for 24 h. Thus, we hypothesize that CDNF may play a role, mediator or inhibitor, in regulating the inflammation in microglial cells induced by LPS. Finally, our data showed that CDNF significantly attenuated the production of proinflammatory cytokines (PGE2 and IL-1?) and remarkably alleviated the cytotoxicity (percentage of lactate dehydrogenase released) in the LPS-induced microglia by suppressing the phosphorylation of JNK, but not the P38 or ERK pathways. These results demonstrate the anti-inflammatory property of CDNF by inhibition of JNK signaling in LPS-induced microglia, suggesting that CDNF may be a potential novel agent for the treatment of neuroinflammation in the CNS disorders. PMID:24078520

Zhao, Hua; Cheng, Lei; Liu, Yi; Zhang, Wen; Maharjan, Sailendra; Cui, Zhaoqiang; Wang, Xingli; Tang, Dongqi; Nie, Lin

2014-02-01

283

Effect of Pump-Induced Density Depletions on the Spectrum of Stimulated Electromagnetic Emissions.  

National Technical Information Service (NTIS)

Analytical formulas describing the standing wave pattern in the ionospheric reflection region of a vertically propagating HF electromagnetic wave in the O mode are used to estimate density depletions due to the ponderomotive force of the successive wave m...

T. B. Leyser B. Thide

1988-01-01

284

Reduced hedonic behavior and altered cardiovascular function induced by mild sodium depletion in rats.  

PubMed

Interactions among sodium homeostasis, fatigue, mood, and cardiovascular regulation have been described previously. The present study investigates the effects of sodium deficiency on an index of mood (hypohedonia; Experiment 1), cardiovascular function (Experiment 2), and plasma electrolytes (Experiment 3) in rats. Following 48 hr of sodium depletion with a diuretic (furosemide) and a sodium deficient diet, rats displayed hypohedonia evidenced by reduced responding for rewarding electrical brain stimulation into the hypothalamus. Also, sodium depletion produced increased heart rate and reduced heart rate variability. Plasma sodium levels were lower in sodium-depleted rats versus control rats, whereas potassium levels were unchanged. Thus, mild sodium depletion produces hypohedonia and cardiovascular alterations, which has implications for understanding behavioral and cardiovascular consequences of sodium deficiency. PMID:17014263

Grippo, Angela J; Moffitt, Julia A; Beltz, Terry G; Johnson, Alan Kim

2006-10-01

285

ATP depletion, purine riboside triphosphate accumulation and rat thymocyte death induced by purine riboside.  

PubMed

Purine riboside (purine-1-D-ribofuranoside, nebularine), an adenosine analog, exerts cytotoxic effect both in vivo and in vitro. However, exact biochemical mechanism for its toxicity and sensitivity of lymphoid cells remains unknown. The present experiments have examined the sequential metabolic changes leading to cell death, induced in cultured rat thymocytes during incubation with purine riboside. Among 22 analogs tested, purine-riboside and tubercidin were most toxic as determined by trypan blue exclusion and lactate dehydrogenase leakage from the cells. 2-Chloroadenosine and 2'-deoxyadenosine were only moderately toxic, whereas other analogs tested were without effect on cell viability. In the presence of purine riboside, more than 90% of ATP was lost after 2 h of incubation. Hypoxanthine accumulated in the medium and the formation of purine-riboside triphosphate exceeded 4-fold the physiological concentration of ATP in the cell. Inhibition of adenosine kinase by 5-iodotubercidin reversed the cytotoxic effect of purine riboside. Interestingly, cells virtually deprived of ATP after 2 h of incubation with purine riboside maintained high nucleotide energy charge value and high viability. Purine riboside triphosphate was capable to replace ATP in stimulation of glycolysis in cell-free thymus extract. We conclude that for a short time (a few hours) purine riboside triphosphate formed in the cell may serve in the absence of ATP as an intermediate of cellular energy metabolism in rat thymocytes. However, possibly due to toxic effects of purine-riboside triphosphate, cells were finally dying. Thus, ATP depletion and adenosine kinase mediated purine riboside phosphates formation are the principle causes of rat thymocytes death exposed to purine riboside. PMID:10079051

Kozlowska, M; Smolenski, R T; Makarewicz, W; Hoffmann, C; Jastorff, B; Swierczynski, J

1999-02-22

286

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

NASA Astrophysics Data System (ADS)

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

Raudino, Antonio; Pannuzzo, Martina; Karttunen, Mikko

2012-02-01

287

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

NASA Technical Reports Server (NTRS)

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

Adams, Gregory R.; Baldwin, Kenneth M.

1995-01-01

288

Dopamine-induced changes in neural network patterns supporting aversive conditioning.  

PubMed

The aim of the present paper is to assess the effects of altered dopamine (DA) transmission on the functional connectivity among brain regions mediating aversive conditioning in humans. To this aim, we analyzed a previous published data set from a double-blind design combined with functional magnetic resonance imaging (fMRI) recordings in which healthy volunteers were randomly assigned to one of three drug groups: amphetamine (an indirect DA agonist), haloperidol (DA D2 receptor antagonist), and placebo. Participants were exposed to an aversive classical conditioning paradigm using cutaneous electrical stimulation as the unconditioned stimulus (US), and visual cues as the conditioned stimuli (CS) where one colour (CS+) was followed by the US in 33% of the trials and another colour (CS-) had no consequences. All participants reported awareness of stimulus contingencies. Group analysis of fMRI data revealed that the left ventral striatum (VS) and amygdala activated in response to the CS+ in all the three groups. Because of their activation patterns and documented involvement in aversive conditioning, both regions were used as seeds in the functional connectivity analysis. To constrain the functional networks obtained to relate to the conditioned response, we also correlated seed activity with the Galvanic Skin Response (GSR). In the placebo group, the right ventral tegmental area/substantia nigra (VTA/SN), bilateral caudate, right parahippocampal gyrus, left inferior parietal lobule (IPL), bilateral postcentral gyrus, bilateral middle frontal (BA 46), orbitofrontal, and ventromedial prefrontal cortices (PFC, BA 10/11) correlated with the VS and amygdala seeds in response to the CS+ compared to the CS-. Enhancing dopamine transmission via amphetamine was associated with reduced task differences and significant functional connectivity for both CS+ and CS- conditions between the left VS seed and regions modulated by DA, such as the left VTA/SN, right caudate, left amygdala, left middle frontal gyrus (BA 46), and bilateral ventromedial PFC (BA 10). Blocking dopamine transmission via haloperidol was associated with significant functional connectivity across an alternate network of regions including the left amygdala seed and the right insula, the left ACC (BA 24/32), bilateral IPL (BA 40), precuneus (BA 7), post-central gyrus, middle frontal gyrus (BA 46), and supplementary motor area (SMA, BA 6) to the CS+ versus the CS-. These data provide insight into the distinct effects of DA agents on the functional connectivity between striatal, limbic, and prefrontal areas. PMID:19961836

Diaconescu, Andreea Oliviana; Menon, Mahesh; Jensen, Jimmy; Kapur, Shitij; McIntosh, Anthony Randal

2010-02-01

289

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

2006-01-01

290

Depleted uranium (92U238) induced preionization for enhanced and reproducible x-ray emission from plasma focus  

Microsoft Academic Search

The effect of preionization induced by depleted uranium (92U238) around the insulator sleeve on the x-ray emission of (2.3-3.9 kJ) plasma focus device is investigated by employing Quantrad Si p-i-n diodes and a multipinhole camera. X-ray emission in 4pi geometry is measured as a function of charging voltage with and without preionization. It is found that the preionization enhances Cu

S. Ahmad; M. Shafiq; M. Zakaullah; A. Waheed

2006-01-01

291

Enhanced and reproducible neutron emission from a plasma focus with pre-ionization induced by depleted uranium (U238)  

Microsoft Academic Search

The effect of pre-ionization induced by depleted uranium (92U238) around the insulator sleeve on the neutron emission of (1.8-3.3 kJ) plasma focus device is investigated by employing time resolved and time integrated neutron detectors. The maximum average neutron yield of 2.5 × 108 is recorded at 3.5 mbar without pre-ionization, which increases up to 3.85 × 108 with pre-ionization. It

S. Ahmad; S. S. Hussain; Mehboob Sadiq; M. Shafiq; A. Waheed; M. Zakaullah

2006-01-01

292

Effect of Serotonin Depletion Induced by p-Chloroamphetamine on Changes in Rats’ Activity Levels Produced by Lithium  

Microsoft Academic Search

The role of serotonin (5-HT) transmission in the production of changes in rats’ activity levels induced by 0.15 and 1.50 mEq\\/kg LiCl was assessed by selectively depleting 5-HT brain levels with p-chloroamphetamine prior to chronic administration of LiCl for 21 days. While p-chloroamphetamine pretreatment decreased 5-HT levels by 56%, irrespective of the fact that the animals had been administered either

P. Cappeliez; N. White; J.-R. Duhamel

1982-01-01

293

Serotonin 2A receptors differentially contribute to abuse-related effects of cocaine and cocaine-induced nigrostriatal and mesolimbic dopamine overflow in nonhuman primates.  

PubMed

Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self-administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug- and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways. PMID:23946394

Murnane, Kevin S; Winschel, Jake; Schmidt, Karl T; Stewart, LaShaya M; Rose, Samuel J; Cheng, Kejun; Rice, Kenner C; Howell, Leonard L

2013-08-14

294

Effect of intravenous captopril on c-fos expression induced by sodium depletion in neurons of the lamina terminalis.  

PubMed

Peripheral administration of the angiotensin converting enzyme (ACE) inhibitor, captopril, and the central infusion of sarile, an angiotensin II (Ang II) receptor antagonist, were used to evaluate the role of renal and brain generated Ang II in sodium depletion-induced production of Fos in cells of the subfornical organ (SFO) and organum vasculosum lamina terminalis (OVLT). Pretreatment with intravenous captopril (100 mg/kg) significantly inhibited the c-fos expression induced by sodium depletion in the SFO and OVLT. In contrast, continuous intracerebroventricular infusion of sarile (22.5 micrograms/4.5 h, 5 microliters/h) did not affect the expected pattern of c-fos expression observed in both nuclei, 4 h after peritoneal dialysis. These results show that systemic interference with the angiotensin system of renal origin by captopril inhibited the production of Fos induced by sodium depletion in cells of the SFO and OVLT. These findings are consistent with the hypothesis that a rise in peripheral Ang II levels, triggered by sodium deficiency, could be an important mediator of the physiological and behavioral responses that lead to the restoration of sodium balance. In addition, this study suggests that increased circulating Ang II levels in response to body sodium deficit can directly stimulate neural pathways in the SFO and OVLT. PMID:9323436

Pastuskovas, C; Vivas, L

1997-01-01

295

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

PubMed

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

1998-09-01

296

Effects of the neurotoxin MPTP and pargyline protection on extracellular energy metabolites and dopamine levels in the striatum of freely moving rats.  

PubMed

The neurotoxin MPTP is known to induce dopamine release and depletion of ATP in the striatum of rats. Therefore, we studied the changes induced by MPTP and pargyline protection both on striatal dopamine release and on extracellular energy metabolites in freely moving rats, using dual asymmetric-flow microdialysis. A dual microdialysis probe was inserted in the right striatum of rats. MPTP (25mg/kg, 15mg/kg, 10mg/kg) was intraperitoneally administered for three consecutive days. MAO-B inhibitor pargyline (15mg/kg) was systemically administered before neurotoxin administration. The first MPTP dose induced an increase in dialysate dopamine and a decrease of DOPAC levels in striatal dialysate. After the first neurotoxin administration, increases in striatal glucose, lactate, pyruvate, lactate/pyruvate (L/P) and lactate/glucose (L/G) ratios were observed. Subsequent MPTP administrations showed a progressive reduction of dopamine, glucose and pyruvate levels with a concomitant further increase in lactate levels and L/P and L/G ratios. At day 1, pargyline pre-treatment attenuated the MPTP-induced changes in all studied analytes. Starting from day 2, pargyline prevented the depletion of dopamine, glucose and pyruvate while reduced the increase of lactate, L/P ratio and L/G ratio. These in vivo results suggest a pargyline neuroprotection role against the MPTP-induced energetic impairment consequent to mitochondrial damage. This neuroprotective effect was confirmed by TH immunostaining of the substantia nigra. PMID:24080403

Bazzu, Gianfranco; Rocchitta, Gaia; Migheli, Rossana; Alvau, Maria Domenica; Zinellu, Manuel; Puggioni, Giulia; Calia, Giammario; Mercanti, Giulia; Giusti, Pietro; Desole, Maria Speranza; Serra, Pier Andrea

2013-11-13

297

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

PubMed Central

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

von Dobeln, Ulrika; Hultenby, Kjell; Isetun, Sindra; Gafvels, Mats; Karlsson, Anna

2013-01-01

298

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.

Xie, Guiqin; Krnjevic, Kresimir; Ye, Jiang-Hong

2013-01-01

299

Dopamine D1 receptors and phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein-32 in the medial preoptic area are involved in experience-induced enhancement of male sexual behavior in rats.  

PubMed

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

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

2012-08-01

300

Nicotine-mediated improvement in L-dopa-induced dyskinesias in MPTP-lesioned monkeys is dependent on dopamine nerve terminal function.  

PubMed

L-dopa-induced dyskinesias (LIDs) are abnormal involuntary movements that develop with long term L-dopa therapy for Parkinson's disease. Studies show that nicotine administration reduced LIDs in several parkinsonian animal models. The present work was done to understand the factors that regulate the nicotine-mediated reduction in LIDs in MPTP-lesioned nonhuman primates. To approach this, we used two groups of monkeys, one with mild-moderate and the other with more severe parkinsonism rendered dyskinetic using L-dopa. In mild-moderately parkinsonian monkeys, nicotine pretreatment (300 ?g/ml via drinking water) prevented the development of LIDs by ~75%. This improvement was maintained when the nicotine dose was lowered to 50 ?g/ml but was lost with nicotine removal. Nicotine re-exposure again decreased LIDs. By contrast, nicotine treatment did not reduce LIDs in monkeys with more severe parkinsonism. We next determined how nicotine's ability to reduce LIDs correlated with lesion-induced changes in the striatal dopamine transporter and (3)H-dopamine release in these two groups of monkeys. The striatal dopamine transporter was reduced to 54% and 28% of control in mild-moderately and more severely parkinsonian monkeys, respectively. However, basal, K(+), ?4?2* and ?6?2* nAChR-evoked (3)H-dopamine release were near control levels in striatum of mild-moderately parkinsonian monkeys. By contrast, these same release measures were reduced to a significantly greater extent in striatum of more severely parkinsonian monkeys. Thus, nicotine best improves LIDs in lesioned monkeys in which striatal dopamine transmission is still relatively intact. These data suggest that nicotine treatment would most effectively reduce LIDs in patients with mild to moderate Parkinson's disease. PMID:23009753

Quik, Maryka; Mallela, Archana; Chin, Matthew; McIntosh, J Michael; Perez, Xiomara A; Bordia, Tanuja

2013-02-01

301

Nicotine-mediated improvement in L-dopa-induced dyskinesias in MPTP-lesioned monkeys is dependent on dopamine nerve terminal function  

PubMed Central

L-Dopa-induced dyskinesias (LIDs) are abnormal involuntary movements that develop with long term L-dopa therapy for Parkinson’s disease. Studies show that nicotine administration reduced LIDs in several parkinsonian animal models. The present work was done to understand the factors that regulate the nicotine-mediated reduction in LIDs in MPTP-lesioned nonhuman primates. To approach this, we used two groups of monkeys, one with mild-moderate and the other with more severe parkinsonism rendered dyskinetic using L-dopa. In mild-moderately parkinsonian monkeys, nicotine pretreatment (300 ?g/ml via drinking water) prevented the development of LIDs by ~75%. This improvement was maintained when the nicotine dose was lowered to 50 ?g/ml but was lost with nicotine removal. Nicotine re-exposure again decreased LIDs. By contrast, nicotine treatment did not reduce LIDs in monkeys with more severe parkinsonism. We next determined how nicotine’s ability to reduce LIDs correlated with lesion-induced changes in the striatal dopamine transporter and 3H-dopamine release in these two groups of monkeys. The striatal dopamine transporter was reduced to 54% and 28% of control in mild-moderately and more severely parkinsonian monkeys, respectively. However, basal, K+, ?4?2* and ?6?2* nAChR-evoked 3H-dopamine release were near control levels in striatum of mild-moderately parkinsonian monkeys. By contrast, these same release measures were reduced to a significantly greater extent in striatum of more severely parkinsonian monkeys. Thus, nicotine best improves LIDs in lesioned monkeys in which striatal dopamine transmission is still relatively intact. These data suggest that nicotine treatment would most effectively reduce LIDs in patients with mild to moderate Parkinson’s disease.

Quik, Maryka; Mallela, Archana; Chin, Matthew; McIntosh, J. Michael; Perez, Xiomara A.; Bordia, Tanuja

2012-01-01

302

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.

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

2014-01-01

303

Depletion of HDAC6 Enhances Cisplatin-Induced DNA Damage and Apoptosis in Non-Small Cell Lung Cancer Cells  

PubMed Central

Histone deacetylase inhibitors (HDACi) are promising therapeutic agents which are currently used in combination with chemotherapeutic agents in clinical trials for cancer treatment including non-small cell lung cancer (NSCLC). However, the mechanisms underlying their anti-tumor activities remain elusive. Previous studies showed that inhibition of HDAC6 induces DNA damage and sensitizes transformed cells to anti-tumor agents such as etoposide and doxorubicin. Here, we showed that depletion of HDAC6 in two NSCLC cell lines, H292 and A549, sensitized cells to cisplatin, one of the first-line chemotherapeutic agents used to treat NSCLC. We suggested that depletion of HDAC6 increased cisplatin-induced cytotoxicity was due to the enhancement of apoptosis via activating ATR/Chk1 pathway. Furthermore, we showed that HDAC6 protein levels were positively correlated with cisplatin IC50 in 15 NSCLC cell lines. Lastly, depletion of HDAC6 in H292 xenografts rendered decreased tumor weight and volume and exhibited increased basal apoptosis compared with the controls in a xenograft mouse model. In summary, our findings suggest that HDAC6 is positively associated with cisplatin resistance in NSCLC and reveal HDAC6 as a potential novel therapeutic target for platinum refractory NSCLC.

Williams, Kendra A.; Dong, Huiqin; Bai, Wenlong; Nicosia, Santo V.; Khochbin, Saadi; Bepler, Gerold; Zhang, Xiaohong

2012-01-01

304

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.

Monnier, Justin; Zabel, Brian A.

2014-01-01

305

Parallel dopamine D1 receptor activity dependence of L-dopa-induced normal movement and dyskinesia in mice  

PubMed Central

L-dopa-induced dyskinesia 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.

Li, Li; Zhou, Fu-Ming

2013-01-01

306

Loss of D2 Dopamine Receptor Function Modulates Cocaine-Induced Glutamatergic Synaptic Potentiation in the Ventral Tegmental Area  

PubMed Central

Potentiation of glutamate responses is a critical synaptic response to cocaine exposure in ventral tegmental area (VTA) neurons. However, the mechanism by which cocaine exposure promotes potentiation of NMDA receptors (NMDARs) and subsequently AMPA receptors (AMPARs) is not fully understood. In this study we demonstrate that repeated cocaine treatment causes loss of D2 dopamine receptor functional responses via interaction with lysosome-targeting G-protein-associated sorting protein1 (GASP1). We also show that the absence of D2 downregulation in GASP1-KO mice prevents cocaine-induced potentiation of NMDAR currents, elevation of the AMPA/NMDA ratio, and redistribution of NMDAR and AMPAR subunits to the membrane. As a pharmacological parallel, coadministration of the high-affinity D2 agonist, aripiprazole, reduces not only functional downregulation of D2s in response to cocaine but also potentiation of NMDAR and AMPAR responses in wild-type mice. Together these data suggest that functional loss of D2 receptors is a critical mechanism mediating cocaine-induced glutamate plasticity in VTA neurons.

Madhavan, Anuradha; Argilli, Emanuela; Bonci, Antonello

2013-01-01

307

Effect of pump-induced density depletions on the spectrum of stimulated electromagnetic emissions  

Microsoft Academic Search

Analytical formulas describing the standing wave pattern in the ionospheric reflection region of a vertically propagating HF electromagnetic wave in the O mode are used to estimate density depletions due to the ponderomotive force of the successive wave maxima. The frequencies of Langmuir waves enhanced through the parametric decay instability in the created density wells are determined. It is suggested

T. B. Leyser; B. Thide

1988-01-01

308

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

NASA Technical Reports Server (NTRS)

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

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

2007-01-01

309

Occupancy of dopamine D 2\\/3 receptors in rat brain by endogenous dopamine measured with the agonist positron emission tomography radioligand [ 11 C]MNPA  

Microsoft Academic Search

Estimates of dopamine D2\\/3 receptor occupancy by endogenous dopa- mine using positron emission tomography (PET) in animals have varied almost three- fold. This variability may have been caused by incomplete depletion of dopamine or by the use of antagonist radioligands, which appear less sensitive than agonist radioli- gands to changes in endogenous dopamine. PET scans were performed in rats with

Nicholas Seneca; Sami S. Zoghbi; Mette Skinbjerg; Jeih-San Liow; Jinsoo Hong; David R. Sibley; Victor W. Pike; Christer Halldin; Robert B. Innis

2008-01-01

310

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

2014-05-01

311

Amino acid containing thapsigargin analogues deplete androgen receptor protein via synthesis inhibition and induce the death of prostate cancer cells.  

PubMed

There are quantitative and/or qualitative mechanisms allowing androgen receptor (AR) growth signaling in androgen ablation refractory prostate cancer cells. Regardless of the mechanism, agents that deplete AR protein expression prevent such AR growth signaling. Thapsigargin (TG) is a highly cell-penetrant sequiterpene-lactone that once inside cells inhibits (IC(50), ? 10 nmol/L) critically important housekeeping SERCA 2b calcium pumps in the endoplasmic reticulum. Using a series of five genetically diverse androgen ablation refractory human prostate cancer lines (LNCaP, LAPC-4, VCaP, MDA-PCa-2b, and CWR22Rv1), TG inhibition of SERCA pumps consistently results in depletion of the endoplasmic reticulum Ca(+2) coupled with ?mol/L elevation in the intracellular free Ca(+2) initiating a molecular cascade that: (a) inhibits Cap-dependent AR protein synthesis resulting in 90% depletion of AR protein by 24 hours of TG exposure, (b) arrests the cells in G(0), and (c) induces their apoptotic death. Unfortunately, due to its highly lipophilic nature, TG is not deliverable as a systemic agent without host toxicity. Therefore, TG analogues containing amino acids were developed, which retain ability to deplete AR protein and induce cell death and which can be covalently linked to peptide carriers producing water soluble prodrugs for systemic delivery. Specific amino acid sequences are used to restrict the liberation of cytotoxic amino acid containing TG analogues from the peptide prodrug by prostate-specific proteases, such as prostate-specific antigen and prostate-specific membrane antigen, or cancer-specific proteases, such as fibroblast activation protein, so that toxicity of these prodrugs is selectively targeted to metastatic sites of prostate cancer. Based on these results, these prodrugs are undergoing clinical development. PMID:19417145

Vander Griend, Donald J; Antony, Lizamma; Dalrymple, Susan L; Xu, Yi; Christensen, S Brogger; Denmeade, Samuel R; Isaacs, John T

2009-05-01

312

Effect of temperature on dopamine transporter function and intracellular accumulation of methamphetamine: implications for methamphetamine-induced dopaminergic neurotoxicity.  

PubMed

Hyperthermia exacerbates and hypothermia attenuates methamphetamine (METH)-induced dopamine (DA) neurotoxicity. The mechanisms underlying these temperature effects are unknown. Given the essential role of the DA transporter (DAT) in the expression 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 test this hypothesis, the effects of small, physiologically relevant temperature changes on DAT function were evaluated in two types of cultured neuronal cells: (1) a neuroblastoma cell line stably transfected with human DAT cDNA and (2) rat embryonic mesencephalic primary cells that naturally express the DAT. Temperatures for studies of DAT function were selected based on core temperature measurements in animals exposed to METH under usual ambient (22 degrees C) and hypothermic (6 degrees C) temperature conditions, where METH neurotoxicity was fully expressed and blocked, respectively. DAT function, determined by measuring accumulation of radiolabeled DA and 1-methyl-4-phenylpyridinium (MPP(+)), was found to directly correlate with temperature, with higher levels of substrate uptake at 40 degrees C, intermediate levels at 37 degrees C, and lower levels at 34 degrees C. DAT-mediated accumulation of METH also directly correlated with temperature, with greater accumulation at higher temperatures. These findings indicate that relatively small, physiologically relevant changes in temperature significantly alter DAT function and intracellular METH accumulation, and suggest that the effect of temperature on METH-induced DA neurotoxicity is mediated, at least in part, at the level of the DAT. PMID:11027249

Xie, T; McCann, U D; Kim, S; Yuan, J; Ricaurte, G A

2000-10-15

313

Neuroprotective effects of the dopamine D 2\\/D 3 agonist pramipexole against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons  

Microsoft Academic Search

We have examined the neuroprotective efficacy of the selective dopamine (DA) D2\\/D3 receptor agonist pramipexole in two models of nigrostriatal (NS) degeneration. The first involves the delayed (28-day) postischemic retrograde NS degeneration that takes place in gerbils following a 10-min episode of bilateral carotid arterial occlusion-induced forebrain ischemia. In vehicle (40% hydroxypropyl cyclodextrin)-treated male gerbils, there was a 40–45% loss

Edward D Hall; Paula K Andrus; Jo A Oostveen; John S Althaus; Philip F Von Voigtlander

1996-01-01

314

Evidence for the Preferential Involvement of 5HT2A Serotonin Receptors in Stress and Drug-Induced Dopamine Release in the Rat Medial Prefrontal Cortex  

Microsoft Academic Search

The mechanism(s) by which serotonin modulates dopamine release in the medial prefrontal cortex is not known, although studies suggest an involvement of 5-HT2 family receptors. We employed in vivo microdialysis and putatively selective 5-HT2A antagonists (M100907, MDL 11,939, SR46349B) to determine if 5-HT2A receptors are responsible for both drug- and stress-induced DA release in the medial prefrontal cortex. MDL 11,939

Elizabeth A Pehek; Christine Nocjar; Bryan L Roth; Tara A Byrd; Omar S Mabrouk

2006-01-01

315

Role of the dopamine transporter in mediating the neuroleptic-induced reduction of tyrosine hydroxylase-immunoreactive midbrain neurons.  

PubMed

We have previously reported a long-term downregulation of midbrain dopaminergic neurons following treatment with neuroleptic medications. The mechanism of this effect is not clear. The dopamine transporter (DAT) has been shown to play a role in the behavioural and biochemical action of neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We postulated a role for the DAT in mediating the changes induced by neuroleptic (i.e., antipsychotic) drugs. In the first experiment, Sprague-Dawley rats simultaneously received twice daily sub-cutaneous injections of either saline or the DAT inhibitor GBR 12909 (GBR; 5 mg/kg/day) and haloperidol (HAL; 2 mg/kg/day) or vehicle. In the second experiment, the animals were treated with daily sub-cutaneous injections of saline or the DAT inhibitor GBR 129091 plus oral risperidone (RISP; 1.5 mg/kg/day) or vehicle. In a third experiment, animals were given normal drinking water or water with clozapine (CLZ, 20 mg/kg/day). Animals were sacrificed immediately after the last treatment. Sections of the substantia nigra (SN) and ventral tegmental area (VTA) were processed for tyrosine hydroxylase (TH) immunoreactivity. Cell counts were analyzed by one-way analysis of variance followed by post-hoc Tukey tests, with significance set at p<0.05. Treatment with HAL or RISP resulted in a significant reduction (HAL 27%; RISP 25%) in the number of TH-immunoreactive cells present in the medial SN pars compacta. This effect was in both cases completely blocked by administration of the DAT inhibitor. In the VTA, TH-positive cell counts were significantly decreased with RISP, but not with HAL. Once again, the RISP-induced changes were blocked by co-administration of the DAT inhibitor. CLZ treatment did not significantly affect TH-positive cell counts in the SN. These results indicate a role for the active dopamine transporter in mediating the suppression of TH expression in midbrain dopaminergic neurons by antipsychotic drugs. DAT inhibitors may prove useful in ameliorating the neurological side effects of antipsychotic medication. PMID:21396352

Reynolds, K B; MacGillivray, L; Zettler, M; Rosebush, P I; Mazurek, M F

2011-06-01

316

Dopamine neurotransmission is involved in the attenuating effects of 5-HT3 receptor antagonist MDL 72222 on acute methamphetamine-induced locomotor hyperactivity in mice.  

PubMed

We have previously shown that 5-HT3 receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. In the present study, we further examined whether the dopaminergic system is involved in the attenuating effects of MDL 72222, a 5-HT3 receptor antagonist, on acute MAP-induced locomotor hyperactivity. For this, we examined alterations of dopamine (DA) in the form of D1 receptor, D2 receptor, and dopamine transporter (DAT) binding labeled with [3H]SCH23390 for D1, [3H]raclopride for D2, and [3H]mazindol for DAT binding in the mouse brains with acute MAP exposure or pretreatment of MDL 72222 with MAP. No significant differences were detected in the D1 receptor, D2 receptor, or DAT binding between any of the groups studied. Interestingly, we found increased DA levels in the striatum following acute MAP exposure; these increased levels were reversed by pretreatment with MDL 72222, but did not affect 5-HT levels in the dorsal raphe. Overall, our results suggest that dopamine neurotransmission plays an important role in the attenuating effects of 5-HT3 receptor antagonist MDL 72222 on acute MAP-induced locomotor hyperactivity in mice. PMID:17948891

Yoo, Ji-Hoon; Nam, Yun-Sun; Lee, Seok-Yong; Jang, Choon-Gon

2008-01-01

317

Chronic ??-tetrahydrocannabinol exposure induces a sensitization of dopamine D?/? receptors in the mesoaccumbens and nigrostriatal systems.  

PubMed

??-tetrahydrocannabinol (THC), through its action on cannabinoid type-1 receptor (CB?R), is known to activate dopamine (DA) neurotransmission. Functional evidence of a direct antagonistic interaction between CB?R and DA D?-receptors (D?R) suggests that D?R may be an important target for the modulation of DA neurotransmission by THC. The current study evaluated, in rodents, the effects of chronic exposure to THC (1?mg/kg/day; 21 days) on D?R and D?R availabilities using the D?R-prefering antagonist and the D?R-preferring agonist radiotracers [ą?F]fallypride and [łH]-(+)-PHNO, respectively. At 24?h after the last THC dose, D?R and D?R densities were significantly increased in midbrain. In caudate/putamen (CPu), THC exposure was associated with increased densities of D?R with no change in D?R mRNA expression, whereas in nucleus accumbens (NAcc) both D?R binding and mRNA levels were upregulated. These receptor changes, which were completely reversed in CPu but only partially reversed in NAcc and midbrain at 1 week after THC cessation, correlated with an increased functionality of D?/?R in vivo, based on findings of increased locomotor suppressive effect of a presynaptic dose and enhanced locomotor activation produced by a postsynaptic dose of quinpirole. Concomitantly, the observations of a decreased gene expression of tyrosine hydroxylase in midbrain together with a blunted psychomotor response to amphetamine concurred to indicate a diminished presynaptic DA function following THC. These findings indicate that the early period following THC treatment cessation is associated with altered presynaptic D?/?R controlling DA synthesis and release in midbrain, with the concurrent development of postsynaptic D?/?R supersensitivity in NAcc and CPu. Such D?/?R neuroadaptations may contribute to the reinforcing and habit-forming properties of THC. PMID:22692568

Ginovart, Nathalie; Tournier, Benjamin B; Moulin-Sallanon, Marcelle; Steimer, Thierry; Ibanez, Vicente; Millet, Philippe

2012-10-01

318

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.

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

2013-01-01

319

Effect of environmental enrichment on methylphenidate-induced locomotion and dopamine transporter dynamics  

PubMed Central

Rats raised in an enriched condition (EC) are less sensitive to the locomotor effects of stimulant drugs than rats raised in an impoverished condition (IC). Methylphenidate (MPD), a primary pharmacotherapy for attention-deficit/hyperactivity disorder, has abuse potential. This study determined whether environmental enrichment differentially altered the effects of MPD on locomotor activity and dopamine (DA) transporter (DAT) function. Acute and repeated MPD (3 or 10 mg/kg, s.c.) increased locomotion in EC, IC and social condition (SC) rats; however, EC rats showed a blunted response to repeated MPD (3 mg/kg). The maximal velocity (Vmax) of [3H]DA uptake in the presence of the combination of phorbol 12-myristate 13-acetate, a protein kinase C (PKC) activator and okadaic acid, a protein phosphatase inhibitor was decreased in EC and IC rats by 68% and 40%, respectively, indicating that DAT in prefrontal cortex (PFC) is more sensitive to PKC-mediated down-regulation in EC rats. Acute MPD (10 mg/kg) administration decreased the Vmax of [3H]DA uptake in PFC and striatum in EC rats, but not in IC rats. Furthermore, [3H]WIN 35,428 binding density was decreased in PFC of EC and IC rats, and in striatum of EC rats given repeated MPD (10 mg/kg). These results demonstrate that environmental enrichment modulates DAT dynamics in PFC. However, since the change in DAT function was observed only following the high dose of MPH (10 mg/kg), the attenuated locomotor response to repeated MPD (3 mg/kg) in EC rats is not likely due to a specific DAT alteration in the brain regions examined.

Wooters, Thomas E.; Bardo, Michael T.; Dwoskin, Linda P.; Midde, Narasimha M.; Gomez, Adrian M.; Mactutus, Charles F.; Booze, Rosemarie M.; Zhu, Jun

2011-01-01

320

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

SciTech Connect

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

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

2011-01-20

321

Sphingomyelin depletion impairs anionic phospholipid inward translocation and induces cholesterol efflux.  

PubMed

The phosphatidylserine (PS) floppase activity (outward translocation) of ABCA1 leads to plasma membrane remodeling that plays a role in lipid efflux to apolipoprotein A-I (apoAI) generating nascent high density lipoprotein. The Tangier disease W590S ABCA1 mutation has defective PS floppase activity and diminished cholesterol efflux activity. Here, we report that depletion of sphingomyelin by inhibitors or sphingomyelinase caused plasma membrane remodeling, leading to defective flip (inward translocation) of PS, higher PS exposure, and higher cholesterol efflux from cells by both ABCA1-dependent and ABCA1-independent mechanisms. Mechanistically, sphingomyelin was connected to PS translocation in cell-free liposome studies that showed that sphingomyelin increased the rate of spontaneous PS flipping. Depletion of sphingomyelin in stably transfected HEK293 cells expressing the Tangier disease W590S mutant ABCA1 isoform rescued the defect in PS exposure and restored cholesterol efflux to apoAI. Liposome studies showed that PS directly increased cholesterol accessibility to extraction by cyclodextrin, providing the mechanistic link between cell surface PS and cholesterol efflux. We conclude that altered plasma membrane environment conferred by depleting sphingomyelin impairs PS flip and promotes cholesterol efflux in ABCA1-dependent and -independent manners. PMID:24220029

Gulshan, Kailash; Brubaker, Gregory; Wang, Shuhui; Hazen, Stanley L; Smith, Jonathan D

2013-12-27

322

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.

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

2011-01-01

323

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

PubMed

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

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

2014-07-01

324

Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of ?1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat  

Microsoft Academic Search

Tesofensine is a novel monoamine reuptake inhibitor that inhibits both norepinephrine, 5-HT, and dopamine (DA) reuptake function. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong effect in obesity management is not clarified. Using a rat model of diet-induced obesity (DIO), we characterized the pharmacological mechanisms underlying the appetite suppressive effect

Anne Marie D Axel; Jens D Mikkelsen; Henrik H Hansen

2010-01-01

325

Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy.  

PubMed

Diabetic nephropathy is the most common cause of end-stage renal disease in the U.S. Recent studies demonstrate that loss of podocytes is an early feature of diabetic nephropathy that predicts its progressive course. Cause and consequences of podocyte loss during early diabetic nephropathy remain poorly understood. Here, we demonstrate that podocyte apoptosis increased sharply with onset of hyperglycemia in Ins2(Akita) (Akita) mice with type 1 diabetes and Lepr(db/db) (db/db) mice with obesity and type 2 diabetes. Podocyte apoptosis coincided with the onset of urinary albumin excretion (UAE) and preceded significant losses of podocytes in Akita (37% reduction) and db/db (27% reduction) mice. Increased extracellular glucose (30 mmol/l) rapidly stimulated generation of intracellular reactive oxygen species (ROS) through NADPH oxidase and mitochondrial pathways and led to activation of proapoptotic p38 mitogen-activated protein kinase and caspase 3 and to apoptosis of conditionally immortalized podocytes in vitro. Chronic inhibition of NADPH oxidase prevented podocyte apoptosis and ameliorated podocyte depletion, UAE, and mesangial matrix expansion in db/db mice. In conclusion, our results demonstrate for the first time that glucose-induced ROS production initiates podocyte apoptosis and podocyte depletion in vitro and in vivo and suggest that podocyte apoptosis/depletion represents a novel early pathomechanism(s) leading to diabetic nephropathy in murine type 1 and type 2 diabetic models. PMID:16380497

Susztak, Katalin; Raff, Amanda C; Schiffer, Mario; Böttinger, Erwin P

2006-01-01

326

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

SciTech Connect

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

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

2011-02-15

327

Isoflurane anesthesia inhibits clozapine- and risperidone-induced dopamine release and anesthesia-induced changes in dopamine metabolism was modified by fluoxetine in the rat striatum: an in vivo microdialysis study.  

PubMed

Previously, we have reported that halothane anesthesia increases the extracellular concentrations of dopamine (DA) metabolites in the rat striatum using in vivo microdialysis techniques, and we have suggested that volatile anesthetics affect DA release and metabolism in various ways. The present investigation assesses the effect of isoflurane, widely used in clinical anesthesia, on DA release and metabolism. A microdialysis probe was implanted in the striatum of male Sprague-Dawley rats (n=5-7 per group). After recovery, the probe was perfused with modified Ringer's solution and 40 microl of dialysate were injected into a high performance liquid chromatograph every 20 min. The rats were given saline or the same volume of 10 mg kg(-1) clozapine, risperidone, fluoxetine or citalopram. After the pharmacological treatment, the rats were anesthetized with 1.0% or 2.5% isoflurane for 1h. The data were analyzed using two-way analysis of variance (ANOVA). For each drug with significant (p<0.05) drug-time interactions, the statistical analysis included one-way ANOVA and Newman-Keuls post hoc comparisons. A high concentration of isoflurane (2.5%) anesthesia increased the extracellular concentration of DA metabolites during emergence from anesthesia. The levels of DA metabolites increased in an isoflurane concentration-dependent manner. Isoflurane attenuated DA release induced by clozapine and risperidone. Fluoxetine, but not citalopram, antagonized the isoflurane-induced increase in metabolites. The results of current investigation suggest that isoflurane enhances presynaptic DA metabolism, and that the oxidation of DA might be partially modulated by the activities of the dopaminergic-serotonergic pathway at a presynaptic site in the rat striatum. PMID:17719143

Adachi, Yushi U; Yamada, Shigeyuki; Satomoto, Maiko; Higuchi, Hideyuki; Watanabe, Kazuhiko; Kazama, Tomiei; Mimuro, Soichiro; Sato, Shigehito

2008-02-01

328

Oxytocin reverses amphetamine-induced deficits in social bonding: evidence for an interaction with nucleus accumbens dopamine.  

PubMed

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

Young, Kimberly A; Liu, Yan; Gobrogge, Kyle L; Wang, Hui; Wang, Zuoxin

2014-06-18

329

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.

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

2012-01-01

330

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-naďve animals and animals with a history of psychostimulant self-administration.

2013-01-01

331

Inhibitory effect of D1-like and D3 dopamine receptors on norepinephrine-induced proliferation in vascular smooth muscle cells  

PubMed Central

The sympathetic nervous system plays an important role in the regulation of blood pressure. There is increasing evidence for positive and negative interactions between dopamine and adrenergic receptors; the activation of the ?-adrenergic receptor induces vasoconstriction, whereas the activation of dopamine receptor induces vasorelaxation. We hypothesize that the D1-like receptor and/or D3 receptor also inhibit ?1-adrenergic receptor-mediated proliferation in vascular smooth muscle cells (VSMCs). In this study, VSMC proliferation was determined by measuring [3H]thymidine incorporation, cell number, and uptake of 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT). Norepinephrine increased VSMC number and MTT uptake, as well as [3H]thymidine incorporation via the ?1-adrenergic receptor in aortic VSMCs from Sprague-Dawley rats. The proliferative effects of norepinephrine were attenuated by the activation of D1-like receptors or D3 receptors, although a D1-like receptor agonist, fenoldopam, and a D3 receptor agonist, PD-128907, by themselves, at low concentrations, had no effect on VSMC proliferation. Simultaneous stimulation of both D1-like and D3 receptors had an additive inhibitory effect. The inhibitory effect of D3 receptor was via protein kinase A, whereas the D1-like receptor effect was via protein kinase C-?. The interaction between ?1-adrenergic and dopamine receptors, especially D1-like and D3 receptors in VSMCs, could be involved in the pathogenesis of hypertension.

Li, Zhen; Yu, Changqing; Han, Yu; Ren, Hongmei; Shi, Weibin; Fu, Chunjiang; He, Duofen; Huang, Lan; Yang, Chengming; Wang, Xukai; Zhou, Lin; Asico, Laureano D.; Zeng, Chunyu; Jose, Pedro A.

2009-01-01

332

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

1997-01-01

333

Targeting Dopamine in Acute Traumatic Brain Injury  

PubMed Central

In addition to the initial mechanical damage, traumatic brain injury (TBI) induces a series of secondary insults, such as, but not limited to, excitotoxicity, metabolic disruption, and oxidative stress. Neuroprotective strategies after TBI have traditionally focused on cellular preservation as the measurable endpoint although multiple lines of evidence indicate that even with significant neuronal sparing deficits remain at both the cellular and behavioral level. As such, the development of therapies that can effectively confer both neuronal sparing and post-injury functional benefit is critical to providing the best treatment options for clinical TBI. Targeting dopaminergic signaling pathways is a novel approach in TBI that provides benefits to both neuronal survival and functional outcomes. Dopamine, like glutamate, can cause oxidative stress and significant cellular dysfunction when either depleted or over-expressed, and also plays an important role in central nervous system inflammation. The purpose of this review is to discuss dopamine in acute TBI and the role that dopaminergic therapies have as neuroprotective strategies.

Bales, James W.; Kline, Anthony E.; Wagner, Amy K.; Dixon, C. Edward

2010-01-01

334

Dopamine D2 Antagonist-Induced Striatal Nur77 Expression Requires Activation of mGlu5 Receptors by Cortical Afferents  

PubMed Central

Dopamine D2 receptor antagonists modulate gene transcription in the striatum. However, the molecular mechanism underlying this effect remains elusive. Here we used the expression of Nur77, a transcription factor of the orphan nuclear receptor family, as readout to explore the role of dopamine, glutamate, and adenosine receptors in the effect of a dopamine D2 antagonist in the striatum. First, we investigated D2 antagonist-induced Nur77 mRNA in D2L receptor knockout mice. Surprisingly, deletion of the D2L receptor isoform did not reduce eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Next, we tested if an ibotenic acid-induced cortical lesion could block the effect of eticlopride on Nur77 expression. Cortical lesions strongly reduced eticlopride-induced striatal upregulation of Nur77 mRNA. Then, we investigated if glutamatergic neurotransmission could modulate eticlopride-induced Nur77 expression. A combination of a metabotropic glutamate type 5 (mGlu5) and adenosine A2A receptor antagonists abolished eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Direct modulation of Nur77 expression by striatal glutamate and adenosine receptors was confirmed using corticostriatal organotypic cultures. Taken together, these results indicate that blockade of postsynaptic D2 receptors is not sufficient to trigger striatal transcriptional activity and that interaction with corticostriatal presynaptic D2 receptors and subsequent activation of postsynaptic glutamate and adenosine receptors in the striatum is required. Thus, these results uncover an unappreciated role of presynaptic D2 heteroreceptors and support a prominent role of glutamate in the effect of D2 antagonists.

Maheux, Jerome; St-Hilaire, Michel; Voyer, David; Tirotta, Emanuele; Borrelli, Emiliana; Rouillard, Claude; Rompre, Pierre-Paul; Levesque, Daniel

2012-01-01

335

Dopamine D(2) Antagonist-Induced Striatal Nur77 Expression Requires Activation of mGlu5 Receptors by Cortical Afferents.  

PubMed

Dopamine D(2) receptor antagonists modulate gene transcription in the striatum. However, the molecular mechanism underlying this effect remains elusive. Here we used the expression of Nur77, a transcription factor of the orphan nuclear receptor family, as readout to explore the role of dopamine, glutamate, and adenosine receptors in the effect of a dopamine D(2) antagonist in the striatum. First, we investigated D(2) antagonist-induced Nur77 mRNA in D(2L) receptor knockout mice. Surprisingly, deletion of the D(2L) receptor isoform did not reduce eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Next, we tested if an ibotenic acid-induced cortical lesion could block the effect of eticlopride on Nur77 expression. Cortical lesions strongly reduced eticlopride-induced striatal upregulation of Nur77 mRNA. Then, we investigated if glutamatergic neurotransmission could modulate eticlopride-induced Nur77 expression. A combination of a metabotropic glutamate type 5 (mGlu5) and adenosine A(2A) receptor antagonists abolished eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Direct modulation of Nur77 expression by striatal glutamate and adenosine receptors was confirmed using corticostriatal organotypic cultures. Taken together, these results indicate that blockade of postsynaptic D(2) receptors is not sufficient to trigger striatal transcriptional activity and that interaction with corticostriatal presynaptic D(2) receptors and subsequent activation of postsynaptic glutamate and adenosine receptors in the striatum is required. Thus, these results uncover an unappreciated role of presynaptic D(2) heteroreceptors and support a prominent role of glutamate in the effect of D(2) antagonists. PMID:22912617

Maheux, Jérôme; St-Hilaire, Michel; Voyer, David; Tirotta, Emanuele; Borrelli, Emiliana; Rouillard, Claude; Rompré, Pierre-Paul; Lévesque, Daniel

2012-01-01

336

Dopamine prevents lipid peroxidation-induced accumulation of toxic ?-synuclein oligomers by preserving autophagy-lysosomal function  

PubMed Central

The formation of Lewy bodies containing ?-synuclein (?-syn), prominent loss of dopaminergic neurons and dopamine (DA) deficiency in substantia nigra and striatum are histopathological and biochemical hallmarks of Parkinson’s disease (PD). Multiple lines of evidence have indicated that a critical pathogenic factor causing PD is enhanced production of reactive oxygen species (ROS), which reacts readily with polyunsaturated fatty acids to cause lipid peroxidation (LPO). LPO products have been shown to facilitate assembly of toxic ?-syn oligomers in in vitro studies. Since DA is prone to autoxidation and cause ROS, it has been suggested that interactions among DA, LPO, and ?-syn play an important role in neuronal loss in PD. However, the exact mechanism(s) remains unclear. We addressed this issue using a neuronal cell model which inducibly expresses human wild-type ?-syn by the tetracycline off (Tet-Off) mechanism and stably expresses high levels of DA transporter. Under retinoic acid elicited neuronal differentiation, cells with or without overexpressing ?-syn and with or without exposure to LPO inducer-arachidonic acid (AA), plus 0–500 ?M of DA were assessed for the levels of LPO, ?-syn accumulation, cell viability, and autophagy. AA exposure elicited similar LPO levels in cells with and without ?-syn overexpression, but significantly enhanced the accumulation of ?-syn oligomers and monomers only in cultures with Tet-Off induction and decreased cell survival in a LPO-dependent manner. Surprisingly, DA at low concentrations (<50 ?M) protected cells from AA cytotoxicity and ?-syn accumulation. Such effects were attributed to the ability of DA to preserve autophagic-lysosomal function compromised by the AA exposure. At high concentrations (>100 ?M), DA exposure enhanced the toxic effects of AA. To our knowledge, this is the first report showing biphasic effects of DA on neuronal survival and ?-syn accumulation.

Jiang, Peizhou; Gan, Ming; Yen, Shu-Hui C.

2013-01-01

337

Depletion of density of states near Fermi energy induced by disorder and electron correlation in alloys  

NASA Astrophysics Data System (ADS)

We have performed high resolution photoemission study of substitutionally disordered alloys Cu-Pt, Cu-Pd, Cu-Ni, and Pd-Pt. The ratios between alloy spectra and pure metal spectra are found to have dips at the Fermi level when the residual resistivity is high and when rather strong repulsive electron-electron interaction is expected. This is in accordance with Altshuler and Aronov's model which predicts depletion of density of states at the Fermi level when both disorder and electron correlation are present.

Noh, Han-Jin; Nahm, Tschang-Uh; Kim, Jae-Young; Park, W.-G.; Oh, S.-J.; Hong, J.-P.; Kim, C.-O.

2000-03-01

338

Trafficking of Na-K-ATPase and dopamine receptor molecules induced by changes in intracellular sodium concentration of renal epithelial cells  

PubMed Central

Most of the transepithelial transport of sodium in proximal tubules occurs through the coordinated action of the apical sodium/proton exchanger and the basolateral Na-K-ATPase. Hormones that regulate proximal tubule sodium excretion regulate the activities of these proteins. We have previously demonstrated that the level of intracellular sodium concentration modulates the regulation of Na-K-ATPase activity by angiotensin II and dopamine. An increase of a few millimolars in intracellular sodium concentration leads to increased Na-K-ATPase activity without a statistically significant increase in the number of plasma membrane Na-K-ATPase molecules, as determined by cell surface protein biotinylation. Using total internal reflection fluorescence, we detected an increased number of Na-K-ATPase molecules in cytosolic compartments adjacent to the plasma membrane, suggesting that the increased intracellular sodium concentration induces a movement of Na-K-ATPase molecules toward the plasma membrane. While intracellular compartments containing Na-K-ATPase molecules are very close to the plasma membrane, compartments containing type 1 dopamine receptors (D1Rs) are distributed in different parts of the cell cytosol. Fluorescence determinations indicate that an increased intracellular sodium concentration induces the increased colocalization of dopamine receptors with Na-K-ATPase molecules in the region of the plasma membrane. We propose that under in vivo conditions, in response to a sodium load in the lumen of proximal tubules, an increased level of intracellular sodium in epithelial cells is an early event that triggers the cellular response that leads to dopamine inhibition of proximal tubule sodium reabsorption.

Cinelli, Angel R.; Efendiev, Riad; Pedemonte, Carlos H.

2008-01-01

339

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

PubMed Central

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

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

2009-01-01

340

Habituation to test procedure modulates the involvement of dopamine D2- but not D1-receptors in ethanol-induced locomotor stimulation in mice  

Microsoft Academic Search

Rationale  Novelty associated with behavioral testing has been shown to enhance psychostimulant- and morphine-induced locomotor stimulation.\\u000a Evidence has demonstrated that novelty increases dopamine (DA) activity, and habituation to a novel environment reduces such\\u000a activation. However, it is not clear whether novelty modulates ethanol-induced behavioral stimulation and whether DA plays\\u000a a role in this effect.\\u000a \\u000a \\u000a \\u000a Objectives  The present work sought to demonstrate a

Raúl Pastor; Marta Miquel; Carlos M. G. Aragon

2005-01-01

341

Role of renal nerves in sodium depletion-induced salt appetite.  

PubMed

The ingestion of water and 0.3 M NaCl solution and the secretion of key hormones were studied in groups of intact and bilaterally renal-denervated rats after extracellular fluid depletion. Hypovolemia with mild hypotension was produced by subcutaneous injections of the diuretic furosemide (10 mg/kg) followed by injections of the angiotensin-converting enzyme inhibitor captopril (5 mg/kg s.c.). Denervated rats drank significantly less of a concentrated saline solution in response to depletion than intact control rats did, but drank similar amounts of water. Denervated rats finished testing in significantly greater negative water and sodium balance compared with controls. Renal denervation did not impair the secretion of renin and aldosterone or the formation of angiotensin I. The diminished sodium intake of denervated rats is not attributable to reduced water and sodium excretion in response to the hypovolemic protocol. These results indicate that the integrity of the renal nerves is important for the normal elaboration of salt appetite in response to hypovolemia/hypotension. PMID:8853406

Thunhorst, R L; Kirby, R F; Johnson, A K

1996-09-01

342

Antisense-Induced Messenger Depletion Corrects a COL6A2 Dominant Mutation in Ullrich Myopathy  

PubMed Central

Abstract Collagen VI gene mutations cause Ullrich and Bethlem muscular dystrophies. Pathogenic mutations frequently have a dominant negative effect, with defects in collagen VI chain secretion and assembly. It is agreed that, conversely, collagen VI haploinsufficiency has no pathological consequences. Thus, RNA-targeting approaches aimed at preferentially inactivating the mutated COL6 messenger may represent a promising therapeutic strategy. By in vitro studies we obtained the preferential depletion of the mutated COL6A2 messenger, by targeting a common single-nucleotide polymorphism (SNP), cistronic with a dominant COL6A2 mutation. We used a 2?-O-methyl phosphorothioate (2?OMePS) antisense oligonucleotide covering the SNP within exon 3, which is out of frame. Exon 3 skipping has the effect of depleting the mutated transcript via RNA nonsense-mediated decay, recovering the correct collagen VI secretion and restoring the ability to form an interconnected microfilament network into the extracellular matrix. This novel RNA modulation approach to correcting dominant mutations may represent a therapeutic strategy potentially applicable to a great variety of mutations and diseases.

Manzati, Elisa; Sabatelli, Patrizia; Passarelli, Chiara; Bovolenta, Matteo; Pellegrini, Camilla; Perrone, Daniela; Squarzoni, Stefano; Pegoraro, Elena; Bonaldo, Paolo; Ferlini, Alessandra

2012-01-01

343

Antisense-induced messenger depletion corrects a COL6A2 dominant mutation in Ullrich myopathy.  

PubMed

Collagen VI gene mutations cause Ullrich and Bethlem muscular dystrophies. Pathogenic mutations frequently have a dominant negative effect, with defects in collagen VI chain secretion and assembly. It is agreed that, conversely, collagen VI haploinsufficiency has no pathological consequences. Thus, RNA-targeting approaches aimed at preferentially inactivating the mutated COL6 messenger may represent a promising therapeutic strategy. By in vitro studies we obtained the preferential depletion of the mutated COL6A2 messenger, by targeting a common single-nucleotide polymorphism (SNP), cistronic with a dominant COL6A2 mutation. We used a 2'-O-methyl phosphorothioate (2'OMePS) antisense oligonucleotide covering the SNP within exon 3, which is out of frame. Exon 3 skipping has the effect of depleting the mutated transcript via RNA nonsense-mediated decay, recovering the correct collagen VI secretion and restoring the ability to form an interconnected microfilament network into the extracellular matrix. This novel RNA modulation approach to correcting dominant mutations may represent a therapeutic strategy potentially applicable to a great variety of mutations and diseases. PMID:22992134

Gualandi, Francesca; Manzati, Elisa; Sabatelli, Patrizia; Passarelli, Chiara; Bovolenta, Matteo; Pellegrini, Camilla; Perrone, Daniela; Squarzoni, Stefano; Pegoraro, Elena; Bonaldo, Paolo; Ferlini, Alessandra

2012-12-01

344

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.

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

2013-01-01

345

Central noradrenergic depletion by DSP-4 prevents stress-induced memory impairments in the object recognition task.  

PubMed

Environmental stress produces adverse affects on memory in humans and rodents. Increased noradrenergic neurotransmission is a major component of the response to stress and noradrenaline (NA) plays an important role in modulating processes involved in learning and memory. The present study investigated the effect of NA depletion on stress-induced changes on memory performance in the mouse. Central NA depletion was induced using the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP-4) and verified by high performance liquid chromatography (HPLC). A novel cage stress procedure involving exposure to a new clean cage for 1 h per day, 4 days per week for 4 weeks, was used to produce stress-induced memory deficits measured using the object recognition task. 50 mg/kg DSP-4 produced large and sustained reductions in NA levels in the frontal cortex and hippocampus measured 24 h, 1 week and 5 weeks after treatment. Four weeks of exposure to novel cage stress induced a memory deficit in the object recognition task which was prevented by DSP-4 pre-treatment (50 mg/kg 1 week before the commencement of stress).These findings indicate that chronic environmental stress adversely affects recognition memory and that this effect is, in part, mediated by the noradrenergic stress response. The implication of these findings is that drugs targeting the noradrenergic system to reduce over-activity may be beneficial in the treatment of stress-related mental disorders such as post-traumatic stress disorder or anxiety in which memory is affected. PMID:19720115

Scullion, G A; Kendall, D A; Sunter, D; Marsden, C A; Pardon, M-C

2009-12-01

346

Antenatal glucocorticoid treatment induces adaptations in adult midbrain dopamine neurons, which underpin sexually dimorphic behavioral resilience.  

PubMed

We demonstrated previously that antenatal glucocorticoid treatment (AGT, gestational days 16-19) altered the size and organization of the adult rat midbrain dopaminergic (DA) populations. Here we investigated the consequences of these AGT-induced cytoarchitectural disturbances on indices of DA function in adult rats. We show that in adulthood, enrichment of striatal DA fiber density paralleled AGT-induced increases in the numbers of midbrain DA neurons, which retained normal basal electrophysiological properties. This was co-incident with changes in (i) striatal D2-type receptor levels (increased, both sexes); (ii) D1-type receptor levels (males decreased; females increased); (iii) DA transporter levels (males increased; females decreased) in striatal regions; and (iv) amphetamine-induced mesolimbic DA release (males increased; females decreased). However, despite these profound, sexually dimorphic changes in markers of DA neurotransmission, in-utero glucocorticoid overexposure had a modest or no effect on a range of conditioned and unconditioned appetitive behaviors known to depend on mesolimbic DA activity. These findings provide empirical evidence for enduring AGT-induced adaptive mechanisms within the midbrain DA circuitry, which preserve some, but not all, functions, thereby casting further light on the vulnerability of these systems to environmental perturbations. Furthermore, they demonstrate these effects are achieved by different, often opponent, adaptive mechanisms in males and females, with translational implications for sex biases commonly found in midbrain DA-associated disorders. PMID:23929547

Virdee, Kanwar; McArthur, Simon; Brischoux, Frédéric; Caprioli, Daniele; Ungless, Mark A; Robbins, Trevor W; Dalley, Jeffrey W; Gillies, Glenda E

2014-01-01

347

Differential effects of micro-opioid, delta-opioid and kappa-opioid receptor agonists on dopamine receptor agonist-induced climbing behavior in mice.  

PubMed

Interactions between the dopaminergic system and opioids have not been adequately clarified. The present study was designed to investigate the effects of micro-opioid (morphine), delta-opioid (SNC80) and kappa-opioid (U50 488H) receptor agonists on dopamine receptor agonist-induced climbing behavior in mice. Apomorphine (dopamine-receptor agonist) increased stereotyped climbing behavior, unlike methamphetamine, morphine, U-50 488H and (+/-)7-hydroxy-N,N-di-n-propyl-2-aminotetralin hydrobromide (D2-like receptor agonist). Furthermore, SKF81297 (D1 receptor agonist) and SNC80 caused climbing behavior. In addition, while morphine (20 mg/kg), but not U50 488H or SNC80, significantly attenuated high-dose apomorphine (2.0 mg/kg)-induced climbing behavior, it significantly potentiated low-dose apomorphine (0.5 mg/kg)-induced climbing behavior. These results suggest that morphine may have dual effects on the behavioral effects induced by apomorphine. Furthermore, we interestingly showed that the combination of apomorphine or SKF81297 and SNC80 enhanced frequent nonstereotypic climbing behavior, suggesting that delta/D1 interactions may play a prominent role in the expression of certain types of behavior in mice. Thus, micro-opioid, delta-opioid and kappa-opioid receptor agonists induce possible differential effects on the dopaminergic system in mice. PMID:17110795

Ito, Shinobu; Mori, Tomohisa; Sawaguchi, Toshiko

2006-12-01

348

Differential effects of the NMDA receptor antagonist MK-801 on dopamine receptor D1- and D2-induced abnormal involuntary movements in a preclinical model.  

PubMed

Dopamine-replacement therapy with l-DOPA is still the gold standard treatment for Parkinson's disease (PD). One drawback is the common development of l-DOPA-induced dyskinesia (LID) in patients, which can be as disabling as the disease itself. There is no satisfactory adjunct therapy available. Glutamatergic transmission in the basal ganglia circuitry has been shown to be an important player in the development of LID. The N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 has previously been shown to reduce l-DOPA-induced abnormal involuntary movements (AIMs) in a rat preclinical model but only at concentrations that worsen parkinsonism. We investigated the contribution of the direct and indirect striatofugal pathways to these effects. In the direct pathway, dopamine D1 receptors (D1R) are expressed, whereas in the indirect pathway, dopamine D2 receptors (D2R) are expressed. We used the 6-hydroxydopamine-lesioned hemi-parkinsonian rat model initially primed with l-DOPA to induce dyskinesia. When the rats were then primed and probed with the D1R agonist SKF81297, co-injection of MK-801 worsened the D1R-induced limb, axial, and orolingual (LAO) AIMs by 18% (predominantly dystonic axial AIMs) but did not aggravate parkinsonian hypokinesia as reflected by a surrogate measure of ipsiversive rotations in this model. In contrast, when the rats were then primed and probed with the D2R agonist quinpirole, co-injection of MK-801 reduced D2R-induced LAO AIMs by 89% while inducing ipsiversive rotations. The data show that only inhibition of the indirect striatopallidal pathway is sufficient for the full anti-dyskinetic/pro-parkinsonian effects of the NMDA receptor antagonist MK-801, and that MK-801 modestly worsens dyskinesias that are due to activation of the direct striatonigral pathway alone. This differential activation of the glutamatergic systems in D1R- and D2R-mediated responses is relevant to current therapy for PD which generally includes a mixture of dopamine agonists and l-DOPA. PMID:24525249

Flores, Andrew J; Bartlett, Mitchell J; So, Lisa Y; Laude, Nicholas D; Parent, Kate L; Heien, Michael L; Sherman, Scott J; Falk, Torsten

2014-04-01

349

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

PubMed Central

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

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

2012-01-01

350

Requirement for the endocannabinoid system in social interaction impairment induced by coactivation of dopamine D1 and D2 receptors in the piriform cortex.  

PubMed

The dopamine receptor family consists of D1-D5 receptors (D1R-D5R), and we explored the contributions of each dopamine receptor subtype in the piriform cortex (PirC) to social interaction impairment (SII). Rats received behavioral tests or electrophysiological recording of PirC neuronal activity after injection of the D1R/D5R agonist SKF38393, the D2R/D3R/D4R agonist quinpirole, or both, with or without pretreatment with dopamine receptor antagonists, D1R or D5R antisense oligonucleotides, the cannabinoid CB1 receptor antagonist AM281, or the endocannabinoid transporter inhibitor VDM11. Systemic injection of SKF38393 and quinpirole together, but not each one alone, induced SII and increased PirC firing rate, which were blocked by D1R or D2R antagonist. Intra-PirC microinfusion of SKF38393 and quinpirole together, but not each one alone, also induced SII, which was blocked by D1R antisense oligonucleotides or D2R antagonist but not by D3R or D4R antagonist or D5R antisense oligonucleotides. SII induced by intra-PirC SKF38393/quinpirole was blocked by AM281 and enhanced by VDM11, whereas neither AM281 nor VDM11 alone affected social interaction behavior. Coadministration of SKF38393 and quinpirole produced anxiolytic effects without significant effects on locomotor activity, olfaction, and acquisition of olfactory short-term memory. These findings suggest that SII induced by coactivation of PirC D1R and D2R requires the endocannabinoid system. PMID:21557291

Zenko, Michelle; Zhu, Yongyong; Dremencov, Eliyahu; Ren, Wei; Xu, Lin; Zhang, Xia

2011-08-01

351

Perinatal asphyxia induces long-term changes in dopamine D1, D2, and D3 receptor binding in the rat brain.  

PubMed

We have investigated the long-term effects of 15-16 min or 19-20 min of perinatal asphyxia on D1, D2, and D3 receptors (analyzed by quantitative autoradiography) in the mesotelencephalic dopamine systems of the 4-week-old rat. Perinatal asphyxia reduced D1 antagonist binding ([3H]SCH 23390 in the presence of ketanserine) in the accumbens nucleus, the olfactory tubercle, and the substantia nigra and increased D1 agonist binding ([3H]dopamine in the presence of spiperone) in the accumbens nucleus and the olfactory tubercle. No changes in D2 antagonist binding ([123]iodosulpride) were found, whereas D2 agonist binding ([3H]N-propylnorapomorphine, [3H]NPA) was reduced in the posterior part of the caudate-putamen, and following 19-20 min of asphyxia it was also reduced in the accumbens nucleus. D3 agonist binding (R/S-(+/-)-2-(N,N-di[2,3(n)-3H] propylamino)-7-hydroxy-1,2,3,4-tetrahydronaphthalene, [3H]7-OH-DPAT) was increased in the anterior part of the caudate-putamen following 15-16 min but not 19-20 min of asphyxia. The results indicate that perinatal asphyxia reduced the number of D1 receptors and increased D1 agonist affinity in the accumbens nucleus and the olfactory tubercle and reduced the number of D1 receptors in the substantia nigra. The number of D2 receptors was unchanged by asphyxia, whereas the D2 agonist affinity was reduced in the caudate-putamen and in the accumbens nucleus. D3 agonist binding was increased in the caudate-putamen selectively following 15-16 min of asphyxia. In conclusion, asphyxia during birth induces long-term changes in the binding characteristics of dopamine receptors in the mesotelencephalic dopamine systems, which may contribute to previously reported behavioral changes. PMID:9225740

Chen, Y; Hillefors-Berglund, M; Herrera-Marschitz, M; Bjelke, B; Gross, J; Andersson, K; von Euler, G

1997-07-01

352

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

PubMed Central

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

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

2011-01-01

353

Dopamine: biphasic dose responses.  

PubMed

The present article indicates that dopamine and/or its agonists induce biphasic dose-response relationships for numerous endpoints. These include locomotion, pain sensitivity, blood pressure, prolactin secretion, oxytocin release, heart rate, memory, and neuronal adenylate cyclase activity. Biphasic responses were reported predominantly with male Sprague-Dawley rats, but also with mice, dogs, monkeys, and humans. Regardless of the model or endpoint the maximum changes from the control were always modest being within the 10 to 80% range. The range of stimulatory responses was quite variable, extending from slightly greater than a factor of 10 for the endpoints such as memory, pain-vocalization, and diastolic blood pressure to the 10(6) range for prolactin release and the 10(8) range for oxytocin release. Mechanistic studies suggested that the stimulatory and inhibitory effects of dopamine are mediated by different receptors or receptor subtypes having opposite actions and different ligand affinities. PMID:11504182

Calabrese, E J

2001-07-01

354

Glutamine depletion induces murine neonatal melena with increased apoptosis of the intestinal epithelium  

PubMed Central

AIM: To investigate the possible biological outcome and effect of glutamine depletion in neonatal mice and rodent intestinal epithelial cells. METHODS: We developed three kinds of artificial milk with different amounts of glutamine; Complete amino acid milk (CAM), which is based on maternal mouse milk, glutamine-depleted milk (GDM), and glutamine-rich milk (GRM). GRM contains three-fold more glutamine than CAM. Eighty-seven newborn mice were divided into three groups and were fed with either of CAM, GDM, or GRM via a recently improved nipple-bottle system for seven days. After the feeding period, the mice were subjected to macroscopic and microscopic observations by immunohistochemistry for 5-bromo-2’-deoxyuridine (BrdU) and Ki-67 as markers of cell proliferation, and for cleaved-caspase-3 as a marker of apoptosis. Moreover, IEC6 rat intestinal epithelial cells were cultured in different concentrations of glutamine and were subject to a 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate cell proliferation assay, flow cytometry, and western blotting to examine the biological effect of glutamine on cell growth and apoptosis. RESULTS: During the feeding period, we found colonic hemorrhage in six of 28 GDM-fed mice (21.4%), but not in the GRM-fed mice, with no differences in body weight gain between each group. Microscopic examination showed destruction of microvilli and the disappearance of glycocalyx of the intestinal wall in the colon epithelial tissues taken from GDM-fed mice. Intake of GDM reduced BrdU incorporation (the average percentage of BrdU-positive staining; GRM: 13.8%, CAM: 10.7%, GDM: 1.14%, GRM vs GDM: P < 0.001, CAM vs GDM: P < 0.001) and Ki-67 labeling index (the average percentage of Ki-67-positive staining; GRM: 24.5%, CAM: 22.4% GDM: 19.4%, GRM vs GDM: P = 0.001, CAM vs GDM: P = 0.049), suggesting that glutamine depletion inhibited cell proliferation of intestinal epithelial cells. Glutamine deprivation further caused the deformation of the nuclear membrane and the plasma membrane, accompanied by chromatin degeneration and an absence of fat droplets from the colonic epithelia, indicating that the cells underwent apoptosis. Moreover, immunohistochemical analysis revealed the appearance of cleaved caspase-3 in colonic epithelial cells of GDM-fed mice. Finally, when IEC6 rat intestinal epithelial cells were cultured without glutamine, cell proliferation was significantly suppressed after 24 h (relative cell growth; 4 mmol/L: 100.0% ± 36.1%, 0 mmol/L: 25.3% ± 25.0%, P < 0.05), with severe cellular damage. The cells underwent apoptosis, accompanied by increased cell population in sub-G0 phase (4 mmol/L: 1.68%, 0.4 mmol/L: 1.35%, 0 mmol/L: 5.21%), where dying cells are supposed to accumulate. CONCLUSION: Glutamine is an important alimentary component for the maintenance of intestinal mucosa. Glutamine deprivation can cause instability of the intestinal epithelial alignment by increased apoptosis.

Motoki, Takayuki; Naomoto, Yoshio; Hoshiba, Junji; Shirakawa, Yasuhiro; Yamatsuji, Tomoki; Matsuoka, Junji; Takaoka, Munenori; Tomono, Yasuko; Fujiwara, Yasuhiro; Tsuchita, Hiroshi; Gunduz, Mehmet; Nagatsuka, Hitoshi; Tanaka, Noriaki; Fujiwara, Toshiyoshi

2011-01-01

355

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.

1988-06-01

356

Age- and location-dependent differences in store depletion-induced h-channel plasticity in hippocampal pyramidal neurons.  

PubMed

Disruptions of endoplasmic reticulum (ER) Ca(2+) homeostasis are heavily linked to neuronal pathology. Depletion of ER Ca(2+) stores can result in cellular dysfunction and potentially cell death, although adaptive processes exist to aid in survival. We examined the age and region dependence of one postulated, adaptive response to ER store-depletion (SD), hyperpolarization-activated cation-nonspecific (h)-channel plasticity in neurons of the dorsal and ventral hippocampus (DHC and VHC, respectively) from adolescent and adult rats. With the use of whole-cell patch-clamp recordings from the soma and dendrites of CA1 pyramidal neurons, we observed a change in h-sensitive measurements in response to SD, induced by treatment with cyclopiazonic acid, a sarcoplasmic reticulum/ER Ca(2+)-ATPase blocker. We found that whereas DHC and VHC neurons in adolescent animals respond to SD with a perisomatic expression of SD h plasticity, adult animals express SD h plasticity with a dendritic and somatodendritic locus of plasticity in DHC and VHC neurons, respectively. Furthermore, SD h plasticity in adults was dependent on membrane potential and on the activation of L-type voltage-gated Ca(2+) channels. These results suggest that cellular responses to the impairment of ER function, or ER stress, are dependent on brain region and age and that the differential expression of SD h plasticity could provide a neural basis for region- and age-dependent disease vulnerabilities. PMID:24381027

Clemens, Ann M; Johnston, Daniel

2014-03-01

357

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

PubMed Central

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

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

2014-01-01

358

Effect of glutathione depletion on caspase-3 independent apoptosis pathway induced by curcumin in Jurkat cells  

Microsoft Academic Search

Curcumin, a yellow pigment from Curcuma longa, exhibits anti-inflammatory, antitumor, and antioxidative properties. Although its precise mode of action has not been elucidated so far, numerous studies have shown that curcumin may induce apoptosis in normal and cancer cells. Previously, we showed that in Jurkat cells curcumin induced nontypical apoptosis-like pathway, which was independent of mitochondria and caspase-3. Now we

Katarzyna Piwocka; Ewa Jaruga; Janusz Skierski; Iwona Gradzka; Ewa Sikora

2001-01-01