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1

Lipopolysaccharide mitagates methamphetamine-induced striatal dopamine depletion via modulating local TNF-? and dopamine transporter expression  

Microsoft Academic Search

Systemic lipopolysaccharide (LPS) treatment may affect methamphetamine (MA)-induced nigrostriatal dopamine (DA) depletion.\\u000a This study was undertaken to determine the critical time window for the protective effects of LPS treatment and the underlying\\u000a mechanisms. An LPS injection (1 mg\\/kg) 72 h before or 2 h after MA treatment [three consecutive, subcutaneous injections of\\u000a MA (10 mg\\/kg each) at 2-h intervals] diminished the MA-induced DA depletion

Yu-Ting Lai; Yen-Ping N. Tsai; Chianfang G. Cherng; Jing-Jer Ke; Ming-Che Ho; Chia-Wen Tsai; Lung Yu

2009-01-01

2

Biphasic Effects of Selegiline on Striatal Dopamine: Lack of Effect on Methamphetamine-Induced Dopamine Depletion  

Microsoft Academic Search

We tested the hypothesis that selegiline can attenuate dopamine depletion if administered following high doses of methamphetamine that cause neurotoxicity in the striatum. Methamphetamine produced decreases of 50% or greater in both striatal concentrations of dopamine and combined concentrations of homovanillic acid and DOPAC in mice. For animals not exposed to methamphetamine, chronic treatment with selegiline over 18 days caused

Kenneth Grasing; Romeu Azevedo; Steven Karuppan; Suchandra Ghosh

2001-01-01

3

25-Hydroxyvitamin D depletion does not exacerbate MPTP-induced dopamine neuron damage in mice.  

PubMed

Recent clinical evidence supports a link between 25-hydroxyvitamin D insufficiency (serum 25-hydroxyvitamin D [25(OH)D] levels <30 ng/mL) and Parkinson's disease. To investigate the effect of 25(OH)D depletion on neuronal susceptibility to toxic insult, we induced a state of 25(OH)D deficiency in mice and then challenged them with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found there was no significant difference between control and 25(OH)D-deficient animals in striatal dopamine levels or dopamine transporter and tyrosine hydroxylase expression after lesioning with MPTP. Additionally, we found no difference in tyrosine hydroxylase expression in the substantia nigra pars compacta. Our data suggest that reducing 25(OH)D serum levels in mice has no effect on the vulnerability of nigral dopaminergic neurons in vivo in this model system of parkinsonism. PMID:22768297

Dean, E Danielle; Mexas, Lydia M; Cápiro, Natalie L; McKeon, Jeanne E; DeLong, Mahlon R; Pennell, Kurt D; Doorn, Jonathan A; Tangpricha, Vin; Miller, Gary W; Evatt, Marian L

2012-07-02

4

DOPAMINE DEPLETION SLOWS RETINAL TRANSMISSION  

EPA Science Inventory

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

5

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

6

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

7

D-amphetamine-induced depletion of energy and dopamine in the rat striatum is attenuated by nicotinamide pretreatment.  

PubMed

The present study examined the effects of nicotinamide on the D-amphetamine (AMPH)-induced dopamine (DA) depletion and energy metabolism change in the rat striatum. In chronic studies, co-administration of AMPH with desipramine, a drug that retards the metabolism of AMPH, (10 mg/kg, intraperitoneal [i.p.], respectively) caused a significant decrease of striatal DA content measured 7 days later. Pretreatment with nicotinamide (500 mg/kg, i.p.), the precursor molecule for the electron carrier molecule nicotinamide adenine dinucleotide (NAD), attenuated this effect of AMPH, whereas itself exerted no long-term effect on striatal DA content. In acute studies, a decrease in striatal adenosine triphospate/adenosine diphosphate (ATP/ADP) ratio was found 3 h after co-injection of AMPH and desipramine. However, nicotinamide pretreatment blocked the reduced striatal ATP/ADP ratio and resulted in a striking increase in striatal NAD content in AMPH-treated rats. Furthermore, nicotinamide was noted to increase striatal ATP/ADP ratio and NAD content in saline-treated rats. These findings suggest that nicotinamide protects against AMPH-induced DAergic neurotoxicity in the striatum of rats via energy supplement. PMID:10566977

Wan, F J; Lin, H C; Kang, B H; Tseng, C J; Tung, C S

1999-10-01

8

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

PubMed Central

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

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

2009-01-01

9

Asymmetrical influence of mesocortical dopamine depletion on stress ulcer development and subcortical dopamine systems in rats: Implications for psychopathology  

Microsoft Academic Search

The effects of left, right or bilateral depletion of the mesocortical dopamine innervation (medial prefrontal and anterior cingulate) with 6-hydroxydopamine were examined in male Sprague-Dawley rats tested for susceptibility to cold restraint-induced gastric stress pathology. All three types of lesions tended to potentiate the development of stress pathology (i.e. ulceration) in comparison to restrained shams, but only right cortical dopamine

R. M. Sullivan; H. Szechtman

1995-01-01

10

Effects of D1 and D2 dopamine receptor antagonists and catecholamine depleting agents on the locomotor stimulation induced by dizocilpine in mice  

Microsoft Academic Search

Low doses of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) induce locomotor stimulation in mice, whereas higher doses are associated with ataxia, stereotyped behaviors and catalepsy. We investigated the role of dopamine receptors and presynaptic dopamine neurons in the locomotor effects of dizocilpine. For comparison, we studied several other drugs that induce locomotor stimulation in mice. Pretreatment of male

Izyaslav P. Lapin; Michael A. Rogawski

1995-01-01

11

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

12

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

13

Effects of Dopamine Depletion on Striatal Neurotensin: Biochemical and lmmunohistochemical Studies  

Microsoft Academic Search

Interactions between striatal dopamine (DA) and neuroten- sin (NT) have been suggested by anatomical, behavioral, and biochemical studies. Nigrostriatal DA neurons, in con- trast to mesocotticolimbic DA neurons, do not appear to contain NT. Thus, distinct neuronal elements subserve in- teractions between DA and NT within the striatum. We have previously demonstrated that reserpine-induced depletion of striatal DA is accompanied

Andrew J. Bean; Ariel Y. Deutch; Robert H. Roth

1999-01-01

14

Effects of D1 and D2 dopamine receptor antagonists and catecholamine depleting agents on the locomotor stimulation induced by dizocilpine in mice.  

PubMed

Low doses of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) induce locomotor stimulation in mice, whereas higher doses are associated with ataxia, stereotyped behaviors and catalepsy. We investigated the role of dopamine receptors and presynaptic dopamine neurons in the locomotor effects of dizocilpine. For comparison, we studied several other drugs that induce locomotor stimulation in mice. Pretreatment of male mice with haloperidol (0.1 mg/kg, i.p.) completely prevented the stimulation of normally coordinated locomotion induced by a non-intoxicating dose of dizocilpine (0.1 mg/kg, i.p.); haloperidol also attenuated the locomotor stimulation produced by phencyclidine (PCP, 1 and 2 mg/kg, i.p.), d-amphetamine (2 and 5 mg/kg, i.p.) and diazepam (0.5 mg/kg, i.p.). Haloperidol (doses up to 2.5 mg/kg) did not attenuate the ataxia and decreased locomotion induced by higher doses of dizocilpine (1 and 2 mg/kg). The active cis isomer of flupenthixol (0.5 mg/kg, i.p.), an antagonist of both D1 and D2 dopamine receptors, also diminished the stimulant actions of all of the test drugs, whereas its inactive trans form did not. The selective D1 antagonist R(+/-)-SCH 23390 (0.1 mg/kg) and the selective D2 antagonist raclopride (1 mg/kg) had little effect on the stimulatory effect of dizocilpine, although they did reduce the stimulation produced by PCP, d-amphetamine and diazepam. However, pretreatment with a combination of R(+/-)SCH 23390 and raclopride completely prevented dizocilpine-induced locomotor stimulation. Pretreatment with alpha-methyl-p-tyrosine (AMPT, 50 and 250 mg/kg), an inhibitor of tyrosine hydroxylase, or with 6-hydroxydopamine (6-OH-DA, 50 micrograms, i.c.v.), a neurotoxin that destroys brain dopaminergic and noradrenergic neurons, did not attenuate the locomotor stimulation induced by dizocilpine, although these treatments did reduce the stimulant effects of d-amphetamine. In AMPT or 6-OH-DA pretreated mice, haloperidol (0.125 mg/kg) prevented the stimulatory effect of dizocilpine. These results support a role for dopamine receptors in the stimulation of normally coordinated locomotion by dizocilpine. However, the locomotor stimulant effect of dizocilpine, unlike that of d-amphetamine, can be expressed in the presence of D1 or D2 dopamine receptor blockade and does not appear to be dependent on intact presynaptic mechanisms. PMID:8561905

Lapin, I P; Rogawski, M A

1995-10-01

15

Gamma-butyrolactone-induced dopamine accumulation in prefrontal cortex is affected by tyrosine availability.  

PubMed

Gamma-butyrolactone (GBL) elevates striatal and prefrontal cortex dopamine levels; only the striatal dopamine levels are elevated by increased dopamine synthesis. If increased dopamine synthesis is necessary in order for dopamine levels to be affected by tyrosine availability, then GBL-induced prefrontal cortex dopamine levels should be tyrosine insensitive. Rats received either vehicle, tyrosine (50 or 200 mg/kg i.p.) or a tyrosine-depleting mixture prior to GBL 750 mg/kg i.p.. GBL-induced dopamine levels in prefrontal cortex were lowered by tyrosine depletion. GBL-induced striatal dopamine levels were not affected. Hence, increased dopamine synthesis may not be necessary in order for tyrosine availability to affect pharmacologically elevated prefrontal cortex dopamine levels. PMID:18606405

Jaskiw, George E; Newbould, Erica; Bongiovanni, Rodolfo

2008-06-08

16

RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion  

Microsoft Academic Search

Parkinson disease is a neurodegenerative disorder whose symptoms are caused by the loss of dopaminergic neurons innervating the striatum. As striatal dopamine levels fall, striatal acetylcholine release rises, exacerbating motor symptoms. This adaptation is commonly attributed to the loss of interneuronal regulation by inhibitory D2 dopamine receptors. Our results point to a completely different, new mechanism. After striatal dopamine depletion,

Jun Ding; Jaime N Guzman; Tatiana Tkatch; Songhai Chen; Joshua A Goldberg; Philip J Ebert; Pat Levitt; Charles J Wilson; Heidi E Hamm; D James Surmeier

2006-01-01

17

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

PubMed Central

Despite evidence that dopamine neurotransmission in the striatum is critical for learning as well as for movement control, little is yet known about how the learning-related dynamics of striatal activity are affected by dopamine depletion, a condition faced in Parkinson’s disease. We made localized intrastriatal 6-hydroxydopamine lesions in rats and recorded within the dopamine-depleted sensorimotor striatal zone and its contralateral correspondent as the animals learned a conditional maze task. Rather than producing global, non-specific elevations in firing rate across the task, the dopamine depletion altered striatal projection neuron activity and fast-spiking interneuron activity selectively, with sharply task-specific and cell-type specific effects, and often, with learning-stage selective effects as well. Striatal projection neurons with strong responses during the maze runs had especially elevated responsiveness during the maze runs. Projection neurons that, instead, fired most strongly prior to maze running showed elevated pre-start firing rates, but not during maze running, as learning progressed. The intrastriatal dopamine depletion severely affected the learning-related patterning of fast-spiking interneuron ensembles, especially during maze running and after extended training. Remarkably, L-DOPA treatment almost entirely reversed the depletion-induced elevations in pre-run firing of the projection neurons, and elevated their responses around start and end of maze runs. By contrast, L-DOPA failed to normalize fast-spiking interneuron activity. Thus the effects of striatal dopamine depletion and restoration on striatal activity are highly dependent not only on cell type, as previously shown, but also on the behavioral activity called for and the state of behavioral learning achieved.

Hernandez, Ledia F.; Kubota, Yasuo; Hu, Dan; Howe, Mark W.; Lemaire, Nune; Graybiel, Ann M.

2013-01-01

18

Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity.  

PubMed

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex. PMID:21584865

Gross, Noah B; Duncker, Patrick C; Marshall, John F

2011-08-31

19

Cortical stimulation evokes abnormal responses in the dopamine-depleted rat basal ganglia  

PubMed Central

The motor cortex (MC) sends massive projections to the basal ganglia. Motor disabilities in patients and animal models of Parkinson’s disease (PD) may be caused by dopamine (DA)-depleted basal ganglia that abnormally process the information originating from MC. To study how DA depletion alters signal transfer in the basal ganglia, MC stimulation-induced (MC-induced) unitary responses were recorded from the basal ganglia of control and 6-hydroxydopamine-treated hemi-parkinsonian rats anaesthetized with isoflurane. This report describes new findings about how DA depletion alters MC-induced responses. MC stimulation evokes an excitation in normally quiescent striatal (Str) neurons projecting to the globus pallidus external segment (GPe). After DA-depletion, the spontaneous firing of Str-GPe neurons increases, and MC stimulation evokes a shorter latency excitation followed by a long lasting inhibition that was invisible under normal conditions. The increased firing activity and the newly exposed long inhibition generate tonic inhibition and a disfacilitation in GPe. The disfacilitation in GPe is then amplified in basal ganglia circuitry and generates a powerful, long inhibition in the basal ganglia output nucleus, the globus pallidus internal segment (GPi). Intra-Str injections of a behaviorally effective dose of DA precursor L-3,4-dihydroxyphenylalanine effectively reversed these changes. These newly observed mechanisms also support the generation of pauses and burst activity commonly observed in the basal ganglia of parkinsonian subjects. These results suggest that the generation of abnormal response sequences in the basal ganglia contributes to the development of motor disabilities in PD and that intra-Str DA supplements effectively suppress abnormal signal transfer.

Kita, Hitoshi; Kita, Takako

2011-01-01

20

Methamphetamine-Induced Neurotoxicity Alters Locomotor Activity, Stereotypic Behavior, and Stimulated Dopamine Release in the Rat  

Microsoft Academic Search

The neurochemical evidence of methamphetamine (MA)- induced toxicity to dopaminergic nerve terminals is well docu- mented; however, the functional consequences are not clearly defined. The present study was designed to investigate whether MA-induced dopamine depletions affect locomotor activity, stereotypic behavior, and\\/or extracellular dopamine concentrations in the neostriatum. Male rats were treated with a neurotoxic regimen of MA (10 mg\\/kg, i.p.,

Tanya L. Wallace; Gary A. Gudelsky; Charles V. Vorhees

1999-01-01

21

Effects of the dopamine stabilizers (S)-(-)-OSU6162 and ACR16 on prolactin secretion in drug-naive and monoamine-depleted rats.  

PubMed

Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus ?-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion. PMID:21533991

Rung, Johan P; Rung, Emilia; Johansson, Anette M; Svensson, Kjell; Carlsson, Arvid; Carlsson, Maria L

2011-05-02

22

Tongue force and tongue motility are differently affected by unilateral vs bilateral nigrostriatal dopamine depletion in rats  

PubMed Central

In addition to its cardinal symptoms of bradykinesia, muscle rigidity, resting tremor and postural disturbances, Parkinson’s disease (PD) also affects orolingual motor function. Orolingual motor deficits can contribute to dysphagia, which increases morbidity and mortality in this population. Previous preclinical studies describing orolingual motor deficits in animal models of PD have focused on unilateral nigrostriatal dopamine (DA) depletion. In this study we compared the effects of unilateral vs bilateral 6-hydroxydopamine (6-OHDA)-induced DA depletion in rats trained to lick water from an isometric force-sensing disc. Rats received either unilateral or bilateral 6-OHDA into the medial forebrain bundle and were tested for four weeks post-lesion. Dependent variables included task engagement (the number of licks per session), tongue force (mean and maximum), and tongue motility (the number of licks per second). While both lesion groups exhibited decreased tongue force output, tongue motility deficits were present in only the group that received unilateral nigrostriatal DA depletion. Task engagement was not significantly diminished by 6-OHDA. Analysis of striatal DA tissue content revealed that DA depletion was ~97% in the unilateral group and ~90% in the bilateral group. These results suggest that while nigrostriatal DA depletion affects tongue force output, deficits in tongue motility may instead result from a functional imbalance in neural pathways affecting this midline structure.

Nuckolls, Andrea L.; Worley, Cole; Leto, Christopher; Zhang, Hongyu; Morris, Jill K.; Stanford, John A.

2012-01-01

23

A rat model of Parkinsonism shows depletion of dopamine in the retina.  

PubMed

The retinal dopamine (DA) deficiency is an important feature of the pathogenesis in Parkinson's disease (PD) visual dysfunction. Systemic inhibition of complex I (rotenone) in rats has been proposed as a model of PD. In this study, we investigated whether systemic inhibition of complex I can induce impairment of DA-ergic cells in the retina, similar to the destruction of retinal cells found in PD patients. Rotenone (2.5mg/kg i.p., daily) was administered over 60 days. Neurochemically, rotenone treated rats showed a depletion of DA in the striatum and substantia nigra (SN). In addition, the number of retinal DA-ergic amacrine cells was significantly reduced in the rotenone treated animals. This study is the first one giving highlight towards a deeper understanding of systemic complex I inhibition (rotenone as an environmental toxin) and the connection between both, DA-ergic degeneration in the nigrostriatal pathway, and in the DA-ergic amacrine cells of the retina. PMID:16962686

Biehlmaier, Oliver; Alam, Mesbah; Schmidt, Werner J

2006-09-08

24

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

PubMed Central

Background Parkinson's disease is a common neurodegenerative disease characterised by progressive loss of dopaminergic neurons, leading to dopamine depletion in the striatum. Mutations in the PINK1 gene cause an autosomal recessive form of Parkinson's disease. Loss of PINK1 function causes mitochondrial dysfunction, increased reactive oxygen species production and calcium dysregulation, which increases susceptibility to neuronal death in Parkinson's disease. The basis of neuronal vulnerability to dopamine in Parkinson's disease is not well understood. Methodology We investigated the mechanism of dopamine induced cell death in transgenic PINK1 knockout mouse neurons. We show that dopamine results in mitochondrial depolarisation caused by mitochondrial permeability transition pore (mPTP) opening. Dopamine-induced mPTP opening is dependent on a complex of reactive oxygen species production and calcium signalling. Dopamine-induced mPTP opening, and dopamine-induced cell death, could be prevented by inhibition of reactive oxygen species production, by provision of respiratory chain substrates, and by alteration in calcium signalling. Conclusions These data demonstrate the mechanism of dopamine toxicity in PINK1 deficient neurons, and suggest potential therapeutic strategies for neuroprotection in Parkinson's disease.

Yao, Zhi; Duchen, Michael R.; Wood, Nicholas W.; Abramov, Andrey Y.

2012-01-01

25

Nucleus accumbens dopamine depletions make animals highly sensitive to high fixed ratio requirements but do not impair primary food reinforcement  

Microsoft Academic Search

It has been suggested that dopamine in nucleus accumbens is involved in the process of enabling organisms to overcome work-related response costs. One way of controlling work costs with operant schedules is to use fixed ratio schedules with different ratio requirements. In the present study, the effects of nucleus accumbens dopamine depletions were investigated using six schedules: fixed ratio 5,

J. D Salamone; A Wisniecki; B. B Carlson; M Correa

2001-01-01

26

Dopamine Agonist 3PPP Fails to Protect Against MPTP-Induced Toxicity  

Microsoft Academic Search

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

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

2004-01-01

27

Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours.  

PubMed

Dopaminergic systems are implicated in stress-related behaviour. Here we investigate behavioural responses to chronic stress in dopamine D2 receptor knockout mice and find that anxiety-like behaviours are increased compared with wild-type mice. Repeated stress exposure suppresses cocaine-induced behavioural sensitization, cocaine-seeking and relapse behaviours in dopamine D2 receptor knockout mice. Cocaine challenge after drug withdrawal in cocaine-experienced wild-type or dopamine D2 receptor knockout mice is associated with inhibition of long-term depression in the nucleus accumbens, and chronic stress during withdrawal prevents inhibition after cocaine challenge in cocaine-experienced dopamine D2 receptor knockout mice, but not in wild-type mice. Lentiviral-induced knockdown of dopamine D2 receptors in the nucleus accumbens of wild-type mice does not affect basal locomotor activity, but confers stress-induced inhibition of the expression of cocaine-induced behavioural sensitization. Stressed mice depleted of dopamine D2 receptors do not manifest long-term depression inhibition. Our results suggest that dopamine D2 receptors have roles in regulating synaptic modification triggered by stress and drug addiction. PMID:23481387

Sim, Hye-Ri; Choi, Tae-Yong; Lee, Hyo Jin; Kang, Eun Young; Yoon, Sehyoun; Han, Pyung-Lim; Choi, Se-Young; Baik, Ja-Hyun

2013-01-01

28

Neural correlates of sleepiness induced by catecholamine depletion  

PubMed Central

Although extensive indirect evidence exists to suggest that the central dopaminergic system plays a significant role in the modulation of arousal, the functional effect of the dopaminergic influence on the regulation of the sleep-wake cycle remains unclear. Thirteen healthy volunteers and 15 unmedicated subjects with a history of major depressive disorder underwent catecholamine depletion (CD) using oral alpha-methyl-para-tyrosine in a randomized, placebo-controlled, double-blind, crossover study. The main outcome measures in both sessions were sleepiness (Stanford-Sleepiness-Scale), cerebral glucose metabolism (positron emission tomography), and serum prolactin concentration. CD consistently induced clinically relevant sleepiness in both groups (p<0.0001). The CD-induced prolactin increase correlated with CD-induced sleepiness (r=0.71, p<0.0001) but not with CD-induced mood and anxiety symptoms (p?0.2). CD-induced sleepiness correlated with CD-induced increases in metabolism in the medial and orbital frontal cortex, bilateral superior temporal cortex, left insula, cingulate motor area and in the vicinity of the periaqueductal gray. This study suggests that the association between dopamine depletion and sleepiness is independent of the brain reward system and the risk for depression. The visceromotor system, the cingulate motor area, the periaqueductal gray and the caudal hypothalamus may mediate the impact of the dopaminergic system on regulation of wakefulness and sleep.

Meyers, Noah; Fromm, Stephen; Luckenbaugh, David A.; Drevets, Wayne C.; Hasler, Gregor

2011-01-01

29

Dopamine and food reward: effects of acute tyrosine/phenylalanine depletion on appetite.  

PubMed

It has been suggested that obese individuals over-eat in order to compensate for deficits in the dopaminergic reward system. The current study used acute tyrosine/phenylalanine depletion (ATPD) to investigate the effect of reduced dopamine function on appetite and the reward value of food in healthy volunteers. The compensatory-eating hypothesis would predict an increase in the reward value and consumption of food following depletion by this method. In a double-blind, counterbalanced, crossover study, 17 male participants (mean age=29.2 (SEM=2.7) years; mean body mass index=24.4 (SEM=0.6) kg/m(2)) were administered with a tyrosine/phenylalanine-free mixture (TYR/PHE-free; depletion condition) and a balanced amino acid mixture (BAL; control). Plasma amino acid levels were measured at baseline and peak depletion (300 min). Appetite, willingness to pay for food, liking, desired portion size and ad libitum food intake were also assessed. The TYR/PHE-free mixture was associated with significant decreases in tyrosine, phenylalanine, and the ratio of tyrosine+phenylalanine to the other large neutral amino acids (all p<.001). There were no effects on our measures of willingness to pay for food or liking. However, in the TYR/PHE-free condition, participants reported significantly lower levels of hunger following a fixed-test meal relative to the BAL condition. In conclusion, we found no evidence for compensatory eating following ATPD. Our results also provide support for the role of dopamine in motivational components of eating. PMID:22230253

Hardman, Charlotte A; Herbert, Vanessa M B; Brunstrom, Jeffrey M; Munafò, Marcus R; Rogers, Peter J

2011-12-30

30

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

PubMed

Exposure to stress alters the behavioral and neurochemical effects of drugs of abuse. However, it is unknown if chronic stress can affect the serotonergic depletions induced by the psychostimulant drug 3,4-methylenedioxymethamphetamine (MDMA). Rats were exposed to 10 days of chronic unpredictable stress (CUS) which resulted in the predicted elevation of basal plasma corticosterone concentrations. On the 11th day, rats received four challenge doses of MDMA (5 mg/kg every 2 h, i.p.) or saline. Five days later, rats were killed and serotonin (5-HT) and dopamine content were measured in the striatum, hippocampus, and frontal cortex. MDMA produced greater depletions of 5-HT in all three brain regions of rats pre-exposed to CUS compared to rats not exposed to CUS. CUS-exposed rats also had an augmented acute hyperthermic response but a similar increase in plasma corticosterone after challenge injections of MDMA compared with non-stressed rats similarly challenged with MDMA. Moreover, CUS-exposed rats exhibited an MDMA-induced depletion of striatal dopamine that was absent in non-stressed rats that received MDMA. To investigate the role of corticosterone in these effects, the corticosterone synthesis inhibitor, metyrapone (50 mg/kg i.p.), was administered prior to each stressor on each of the 10 days of CUS. Metyrapone blocked the chronic stress-induced elevation in basal plasma corticosterone, prevented the enhancement of MDMA-induced hyperthermia, and blocked the enhanced depletions of 5-HT and dopamine in CUS-exposed rats, but had no effect on the acute MDMA-induced increases in plasma corticosterone. These findings suggest that CUS alone can increase the basal level of corticosterone that in turn, plays an important role in enhancing the sensitivity of both 5-HT and dopamine terminals to the hyperthermic and monoamine depleting effects of MDMA without altering the acute corticosterone response to an MDMA challenge. PMID:19409219

Johnson, B N; Yamamoto, B K

2009-02-03

31

Surface-relevant regulable DNA toroids induced by dopamine.  

PubMed

Dopamine (2-(3,4-dihydroxyphenyl)ethylamine) is known as a natural chemical neurotransmitter and is also a cytotoxic and genotoxic molecule for cell apoptosis. In this work, the interaction of DNA with dopamine was investigated. Though the electrostatic interaction of DNA and dopamine was weak in aqueous solution, dopamine condensed circular pBR322 DNA into toroids on the mica surface cooperatively with ethanol. The formed DNA toroids came from the shrinking of DNA that was driven by ethanol-enhanced DNA-dopamine electrostatic interaction. The size of the DNA toroids could be modulated by varying the concentration of dopamine. This study offers useful information about the DNA condensation induced by monovalent cations and the sample preparation for AFM measurement and application. On the other hand, this work provides the potential strategies to prepare morphology and size controllable DNA condensates, which have valuable applications in gene transfection and nanotechnology. PMID:19344139

Guo, Cunlan; Liu, Zhelin; Xu, Fugang; Sun, Lanlan; Sun, Yujing; Yang, Tao; Li, Zhuang

2009-04-30

32

Regulation of intracellular dopamine levels by dopaminergic drugs: Involvement of vesicular monoamine transporter  

Microsoft Academic Search

Endogenous dopamine could serve as a susceptibility factor for dopaminergic neuronal death. Our previous study demonstrated that depletion of dopamine content induced by dopamine receptor agonist was relevant to neuroprotection. In the current study, we have investigated the mechanisms underlying the dopamine-lowering effect of dopaminergic drugs using pheochromocytoma (PC12) cells. The majority of agonistic or antagonistic ligands for the dopamine

Yasuhiko Izumi; Noriyuki Yamamoto; Toshiaki Kume; Hiroshi Katsuki; Hideyuki Sawada; Akinori Akaike

2008-01-01

33

Cysteamine-induced depletion of somatostatin and prolactin  

SciTech Connect

Cysteamine (2-aminoethanethiol (CSH), given in vivo or in vitro, rapidly but reversibly depletes immunoreactive somatostatin (irSS) in the central nervous system and gut as well as biological and immunological prolactin (PRL) activity in both the anterior pituitary and blood of the rat. This depletion of irSS and PRL is dose dependent and cannot be accounted for by release of either compound. Basal and potassium-stimulated SS release is reduced from hypothalamic tissue in vitro in CSH-treated animals. PRL secretion induced both pharmacologically and physiologically is abolished after CSH administration. Furthermore, CSH reduces cellular PRL content in a number of hyperprolactinemic states. The mechanism by which CSH reduces PRL levels is not clear, but it does not appear to act through the dopamine receptor nor does it alter the morphological structure of the lactotrope in normal animals. Most likely, CSH acts by interacting with the disulfide bonds of PRL, thus rendering the molecule both immunologically and biologically inactive.

Millard, W.J.; Sagar, S.M.; Martin, J.B.

1985-06-01

34

Polymer-induced entropic depletion potential  

NASA Astrophysics Data System (ADS)

We study the effective interactions between nanoparticles immersed in an athermal polymer solution using Molecular dynamics. The directly measured polymer-induced depletion forces are well described with a scaling model in which the attraction between particles is caused by the depletion of concentration blobs and thus independent of the length of the polymer chains. We find strong evidence for a repulsive barrier which arises when the distance between the particles is of the order of the correlation length of the solution and which can be interpreted as a packing effect of concentration blobs. Interestingly, the scaling picture can be extended into the regime in which higher virial coefficients of the polymer solution become relevant. We derive a universal relation between the attraction force at the particle contact, f(0), and the osmotic pressure ? as f(0)˜?2/3, demonstrating its validity over a wide range of concentrations of the polymer solution.

Cao, Xue-Zheng; Merlitz, Holger; Wu, Chen-Xu; Sommer, Jens-Uwe

2011-10-01

35

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

Microsoft Academic Search

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

Lars Ståhle

1992-01-01

36

Monoamine release from dopamine-depleted rat caudate nucleus reinnervated by substantia nigra transplants: an in vivo electrochemical study.  

PubMed

Previous studies have shown that fetal substantia nigra (SN) transplanted into a cavity overlying a dopamine (DA)-denervated caudate nucleus can reverse a number of the behavioral abnormalities induced by the denervation. While some histochemical and physiological evidence suggests that this reversal is the result of a functional DA input from the transplant to the host brain, there is little direct evidence for transmitter release from ingrowing graft-derived nerve fibers. In the present work in vivo electrochemistry was used to analyse the magnitude, time course and spatial distribution of neurotransmitter releases evoked by local application of potassium (K+) from DA-depleted, SN transplant-reinnervated striatum. Animals were injected unilaterally with 6-hydroxydopamine (6-OHDA) into the SN and screened by measuring apomorphine-induced rotation. Some were then given SN grafts, which were placed in a 'delayed cavity' just dorsal to the lesioned striatum. Nafion-coated graphite epoxy capillary (GEC) electrodes were employed for the electrochemistry to minimize signals derived from ascorbate or acidic DA metabolites. The GEC electrode was fixed to a K+-filled micropipette and this assembly was used to map the caudate nucleus of control, 6-OHDA-treated, and 6-OHDA-treated, grafted animals. The morphometric relationships between striatal recording sites and transplant location were subsequently verified histologically. Releases from striatal sites within 1.0 mm of the SN grafts were slightly, but not significantly, less than those obtained from control caudate.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:4041791

Rose, G; Gerhardt, G; Strömberg, I; Olson, L; Hoffer, B

1985-08-19

37

Implication of brain-derived neurotrophic factor in the release of dopamine and dopamine-related behaviors induced by methamphetamine  

Microsoft Academic Search

It is widely recognized that methamphetamine enhances the release of dopamine at dopaminergic neuron terminals of the mesolimbic system, which induces dopamine-related behaviors. Brain-derived neurotrophic factor (BDNF), a neurotrophin, binds to and activates its specific receptor tyrosine kinase, TrkB. BDNF has been shown to influence the release of dopamine in the mesolimbic dopamine system. The present study was designed to

M Narita; K Aoki; M Takagi; Y Yajima; T Suzuki

2003-01-01

38

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

39

Intact risk-based decision making in rats with prefrontal or accumbens dopamine depletion.  

PubMed

The medial prefrontal cortex (mPFC) and the core region of the nucleus accumbens (AcbC) are key regions of a neural system that subserves risk-based decision making. Here, we examined whether dopamine (DA) signals conveyed to the mPFC and AcbC are critical for risk-based decision making. Rats with 6-hydroxydopamine or vehicle infusions into the mPFC or AcbC were examined in an instrumental task demanding probabilistic choice. In each session, probabilities of reward delivery after pressing one of two available levers were signaled in advance in forced trials followed by choice trials that assessed the animal's preference. The probabilities of reward delivery associated with the large/risky lever declined systematically across four consecutive blocks but were kept constant within four subsequent daily sessions of a particular block. Thus, in a given session, rats need to assess the current value associated with the large/risky versus small/certain lever and adapt their lever preference accordingly. Results demonstrate that the assessment of within-session reward probabilities and probability discounting across blocks were not altered in rats with mPFC and AcbC DA depletions, relative to sham controls. These findings suggest that the capacity to evaluate the magnitude and likelihood of rewards associated with alternative courses of action seems not to rely on intact DA transmission in the mPFC or AcbC. PMID:22923036

Mai, Bettina; Hauber, Wolfgang

2012-12-01

40

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

41

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

PubMed Central

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

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

2012-01-01

42

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

PubMed

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

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

2012-12-05

43

Dopamine release from serotonergic nerve fibers is reduced in L-DOPA-induced dyskinesia  

PubMed Central

L-DOPA (3,4-dihydroxyphenyl-L-alanine) is the most commonly used treatment for symptomatic control in patients with Parkinson’s disease. Unfortunately, most patients develop severe side effects, such as dyskinesia, upon chronic L-DOPA treatment. The patophysiology of dyskinesia is unclear, however, involvement of serotonergic nerve fibers in converting L-DOPA to dopamine has been suggested. Therefore, potassium-evoked dopamine release was studied after local application of L-DOPA in the striata of normal, dopamine- and dopamine/serotonin-lesioned L-DOPA naïve, and dopamine-denervated chronically L-DOPA-treated dyskinetic rats using in vivo chronoamperometry. The results revealed that local L-DOPA administration into normal and intact hemisphere of dopamine-lesioned L-DOPA naïve animals significantly increased the potassium-evoked dopamine release. L-DOPA application also increased the dopamine peak amplitude in the dopamine-depleted L-DOPA naïve striatum, although these dopamine levels were several-folds lower than in the normal striatum, while no increased dopamine release was found in the dopamine/serotonin-denervated striatum. In dyskinetic animals, local L-DOPA application did not affect the dopamine release, resulting in significantly attenuated dopamine levels compared to those measured in L-DOPA naïve dopamine-denervated striatum. To conclude, L-DOPA is most likely converted to dopamine in serotonergic nerve fibers in the dopamine-depleted striatum, but the dopamine release is several-fold lower than in normal striatum. Furthermore, L-DOPA loading does not increase the dopamine release in dyskinetic animals as found in L-DOPA naïve animals, despite similar density of serotonergic innervation. Thus, the dopamine overflow produced from the serotonergic nerve fibers appears not to be the major cause of dyskinetic behavior.

Nevalainen, Nina; af Bjerken, Sara; Lundblad, Martin; Gerhardt, Greg A.; Stromberg, Ingrid

2011-01-01

44

Physiology of the normal and dopamine-depleted basal ganglia: insights into levodopa pharmacotherapy.  

PubMed

Dopamine (DA) neurons exist in two activity states; either spontaneously firing or quiescent and nonfiring. When faced with a behavioral demand, the quiescent DA neurons can be activated to facilitate normal motor output. Levodopa appears to increase DA output by activating these nonfiring neurons; as a consequence, DA release is increased, but behavioral demand can now overwhelm the system, potentially leading to the inactivation and on/off phenomena. Levodopa administered in a pulsatile manner may also lead to the induction of synaptic plasticity within the DA systems. In the ventral mesolimbic system, this could lead to the loss of behavioral flexibility, impulsive behavior, and cognitive impairment, whereas in the dorsal nigrostriatal system, this may underlie Levodopa-induced dyskinesia. Continuous administration of Levodopa may circumvent this sensitization process, enabling a therapeutic response without limbic and motor side effects. PMID:18781673

Grace, Anthony A

2008-01-01

45

Dopamine precursor depletion impairs timing in healthy volunteers by attenuating activity in putamen and supplementary motor area.  

PubMed

Neuropsychological investigations of patients with Parkinson's disease, schizophrenia, or attention deficit disorder converge with psychopharmacological studies in animals and healthy volunteers to implicate dopamine (DA) pathways in timing. In parallel, single-cell recording and functional neuroimaging studies have highlighted the importance of basal ganglia, prefrontal cortex, and supplementary motor area (SMA) for timing. In a placebo-controlled, within-subject design, we combined event-related functional magnetic resonance imaging with a DA manipulation (acute phenylalanine/tyrosine depletion; APTD) in healthy volunteers to pinpoint the neuroanatomical and functional substrates of the DA modulation of timing. Behaviorally, APTD selectively impaired accuracy of perceptual timing, with no effect on performance of a color-control task matched for difficulty, working memory (WM), and attentional demands. Neurally, APTD attenuated timing-specific activity in the putamen and SMA. Notably, APTD-induced decreases in brain activity were directly correlated to APTD-induced impairments in timing performance. Moreover, APTD modulated timing-specific activity selectively during initial storage of the sample duration, but had no effect during its subsequent retrieval or comparison to a probe. Our results do not simply reflect DA modulation of WM since the color task controlled for the WM updating process necessary for timing of durations in the seconds range. Moreover, preliminary evidence indicated APTD effects on putamen and SMA were greater for subsecond (540 ms) than suprasecond (1080 ms) durations, when WM demands would actually be lower. Instead, we show for the first time in healthy humans that DA manipulation perturbs timing by attenuating the activity in putamen and SMA that mediates initial storage of temporal information into WM. PMID:23175824

Coull, Jennifer T; Hwang, Hye J; Leyton, Marco; Dagher, Alain

2012-11-21

46

Regulation of Dopamine-Induced Natriuresisby the Dopamine-Metabolizing Enzyme Catechol-O-Methyltransferase  

Microsoft Academic Search

Dopamine (DA) is an intrarenal natriuretic hormone involved in sodium homeostasis. A study was performed to elucidate two possible regulatory pathways of DA-induced natriuresis, i.e., metabolism and precursor delivery. This was done by use of an intraperitoneal injection of a catechol-O-methyltransferase (COMT) inhibitor, entacapone, or intravenous infusion of the DA precursor, L-dopa. Entacapone (30 mg\\/kg i.p.) induced a more than

Cecilia Odlind; Viktoria Göransson; Ilkka Reenilä; Peter Hansell

1999-01-01

47

The structure of dopamine induced ?-synuclein oligomers  

Microsoft Academic Search

Inclusions of aggregated ?-synuclein (?-syn) in dopaminergic neurons are a characteristic histological marker of Parkinson’s\\u000a disease (PD). In vitro, ?-syn in the presence of dopamine (DA) at physiological pH forms SDS-resistant non-amyloidogenic oligomers.\\u000a We used a combination of biophysical techniques, including sedimentation velocity analysis, small angle X-ray scattering (SAXS)\\u000a and circular dichroism spectroscopy to study the characteristics of ?-syn oligomers

Agata Rekas; Robert B. Knott; Anna Sokolova; Kevin J. Barnham; Keyla A. Perez; Colin L. Masters; Simon C. Drew; Roberto Cappai; Cyril C. Curtain; Chi L. L. Pham

2010-01-01

48

Nifedipine prevents iron accumulation and reverses iron-overload-induced dopamine neuron degeneration in the substantia nigra of rats.  

PubMed

The mechanisms of iron accumulation in substantia nigra (SN) of Parkinson's diseases remain unclear. The objective of this study was to investigate effects of nifedipine on iron-overload-induced iron accumulation and neurodegeneration in SN of rats. By high performance liquid chromatography-electrochemical detection, tyrosine hydroxylase (TH) immunohistochemistry, and iron content array, we first quantified iron content and the number of dopamine neurons in SN of experimental rats treated with iron dextran. We further assessed effects of treatment with nifedipine. Our results showed that nifedipine treatment prevents iron dextran-induced dopamine depletion in the striatum. Consistently, we found that nifedipine restores the number of TH-positive neurons reduced by iron dextran overload and prevents increase of iron content in the SN. These results suggested that nifedipine may suppress iron toxicity in dopamine neurons and prevent neurodegeneration. PMID:22259026

Ma, ZeGang; Zhou, Yu; Xie, JunXia

2012-01-19

49

Hypoinsulinemia Regulates Amphetamine-Induced Reverse Transport of Dopamine  

PubMed Central

The behavioral effects of psychomotor stimulants such as amphetamine (AMPH) arise from their ability to elicit increases in extracellular dopamine (DA). These AMPH-induced increases are achieved by DA transporter (DAT)-mediated transmitter efflux. Recently, we have shown that AMPH self-administration is reduced in rats that have been depleted of insulin with the diabetogenic agent streptozotocin (STZ). In vitro studies suggest that hypoinsulinemia may regulate the actions of AMPH by inhibiting the insulin downstream effectors phosphotidylinositol 3-kinase (PI3K) and protein kinase B (PKB, or Akt), which we have previously shown are able to fine-tune DAT cell-surface expression. Here, we demonstrate that striatal Akt function, as well as DAT cell-surface expression, are significantly reduced by STZ. In addition, our data show that the release of DA, determined by high-speed chronoamperometry (HSCA) in the striatum, in response to AMPH, is severely impaired in these insulin-deficient rats. Importantly, selective inhibition of PI3K with LY294002 within the striatum results in a profound reduction in the subsequent potential for AMPH to evoke DA efflux. Consistent with our biochemical and in vivo electrochemical data, findings from functional magnetic resonance imaging experiments reveal that the ability of AMPH to elicit positive blood oxygen level–dependent signal changes in the striatum is significantly blunted in STZ-treated rats. Finally, local infusion of insulin into the striatum of STZ-treated animals significantly recovers the ability of AMPH to stimulate DA release as measured by high-speed chronoamperometry. The present studies establish that PI3K signaling regulates the neurochemical actions of AMPH-like psychomotor stimulants. These data suggest that insulin signaling pathways may represent a novel mechanism for regulating DA transmission, one which may be targeted for the treatment of AMPH abuse and potentially other dopaminergic disorders.

Williams, Jason M; Owens, W. Anthony; Turner, Gregory H; Saunders, Christine; Dipace, Concetta; Blakely, Randy D; France, Charles P; Gore, John C; Daws, Lynette C; Avison, Malcolm J; Galli, Aurelio

2007-01-01

50

Polymer induced depletion potentials in polymer-colloid mixtures  

Microsoft Academic Search

The depletion interactions between two colloidal plates or between two colloidal spheres, induced by interacting polymers in a good solvent, are calculated theoretically and by computer simulations. A simple analytical theory is shown to be quantitatively accurate for the case of two plates. A related depletion potential is derived for two spheres; it also agrees very well with direct computer

A. A. Louis; P. G. Bolhuis; E. J. Meijer; J. P. Hansen

2002-01-01

51

Boosting Focally-Induced Brain Plasticity by Dopamine  

Microsoft Academic Search

Dopamine (DA) simultaneously produces both excitation and inhi- bition in the human cortex. In order to shed light on the functional significance of these seemingly opposing effects, we administered the DA precursor levodopa (L-dopa) to healthy subjects in conjunc- tion with 2 neuroplasticity-inducing motor cortex stimulation proto- cols. Transcranial direct current stimulation (tDCS) induces cortical excitability enhancement by anodal and

Min-Fang Kuo; Walter Paulus; Michael A. Nitsche

2008-01-01

52

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

53

DopamineDepletionDoesNotProtectagainstAcute 1Methyl4Phenyl1,2,3,6-TetrahydropyridineToxicity InVivo  

Microsoft Academic Search

Dopamine (DA) has been postulated to play a role in the loss of dopaminergic substantia nigra (SN) neurons in Parkinson's disease becauseofitspropensitytooxidizeandformquinonesandotherreactiveoxygenspeciesthatcanaltercellularfunction.Moreover,DA depletion can attenuate dopaminergic cell loss in vitro. To test the contribution of DA to SN impairment in vivo, we used DA-deficient mice, which lack the enzyme tyrosine hydroxylase in dopaminergic cells, and mice pharmacologically depleted of DA

Francisco A. Perez

54

Striatal dopamine depletion, tremors, and hypokinesia following the intracranial injection of S -adenosylmethionine  

Microsoft Academic Search

The major symptoms of Parkinson disease (PD) are tremors, hypokinesia, rigidity, and abnormal posture, caused by the degeneration\\u000a of dopamine (DA) neurons in the substantia nigra (SN) and deficiency of DA in the neostriatal DA terminals. Norepinephrine\\u000a (NE) and serotonin (5-HT) levels in the neostriatum and tyrosine hydroxylase and melanin pigments in the substantia nigra\\u000a are also decreased, and brain

Clivel G. Charlton; Bernard Crowell

1995-01-01

55

Drosophila D1 dopamine receptor mediates caffeine-induced arousal  

PubMed Central

The arousing and motor-activating effects of psychostimulants are mediated by multiple systems. In Drosophila, dopaminergic transmission is involved in mediating the arousing effects of methamphetamine, although the neuronal mechanisms of caffeine (CAFF)-induced wakefulness remain unexplored. Here, we show that in Drosophila, as in mammals, the wake-promoting effect of CAFF involves both the adenosinergic and dopaminergic systems. By measuring behavioral responses in mutant and transgenic flies exposed to different drug-feeding regimens, we show that CAFF-induced wakefulness requires the Drosophila D1 dopamine receptor (dDA1) in the mushroom bodies. In WT flies, CAFF exposure leads to downregulation of dDA1 expression, whereas the transgenic overexpression of dDA1 leads to CAFF resistance. The wake-promoting effects of methamphetamine require a functional dopamine transporter as well as the dDA1, and they engage brain areas in addition to the mushroom bodies.

Andretic, Rozi; Kim, Young-Cho; Jones, Frederick S.; Han, Kyung-An; Greenspan, Ralph J.

2008-01-01

56

Increased beta activity in dystonia patients after drug-induced dopamine deficiency.  

PubMed

Several studies have confirmed that subthalamic and pallidal local field potential activity in the beta frequency band (13-30 Hz) is exaggerated in untreated patients with Parkinson's disease (PD) and is suppressed by dopaminergic treatment. This particular spectral pattern differs from that in patients with dystonia in whom pallidal activity is prominent at low frequencies (<12 Hz). Here we demonstrate that tetrabenazine induced monoamine depletion and dopamine blockade is associated with increased activity in the low beta band (13-20 Hz) in the internal pallidum of patients with dystonia. Beta activity was elevated in six patients treated with tetrabenazine compared to six patients in whom this drug was not used. Our findings suggest that beta activity is enhanced in the chronically dopamine-depleted and blocked state irrespective of the underlying pathology, consistent with the idea that excessive synchrony in the beta band is directly related to dopaminergic hypofunction, rather than some degenerative disease-specific attribute of Parkinson's disease. PMID:18760276

Kühn, Andrea A; Brücke, Christof; Schneider, Gerd-Helge; Trottenberg, Thomas; Kivi, Anatol; Kupsch, Andreas; Capelle, H Holger; Krauss, Joachim K; Brown, Peter

2008-08-07

57

Methamphetamine-induced dopamine terminal deficits in the nucleus accumbens are exacerbated by reward-associated cues and attenuated by CB1 receptor antagonism.  

PubMed

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. PMID:22306525

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

2012-01-25

58

Dopamine and Spatial Working Memory in Rats and Monkeys: Pharmacological Reversal of Stress-Induced Impairment  

Microsoft Academic Search

The anxiogenic benzodiazepine inverse agonist FG7142 in- creases dopamine turnover in rodent prefrontal cortex but not in other dopamine terminal field areas. FG7142-induced in- creases in prefrontal cortical dopamine receptor stimulation impair prefrontal-dependent, but not nonprefrontal-dependent, cognitive tasks in rats and monkeys. The degree of impairment correlates with levels of prefrontal cortical dopamine turnover in rats and can be blocked

Beth L. Murphy; Amy F. T. Arnsten; J. David Jentsch; Robert H. Roth

1996-01-01

59

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

Microsoft Academic Search

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

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

1996-01-01

60

Phosphodiesterase 10A controls D1-mediated facilitation of GABA release from striato-nigral projections under normal and dopamine-depleted conditions.  

PubMed

In the present study, we found that PDE10A inhibitor papaverine, alone or in combination with the D1 receptor agonist SKF38393, did not change spontaneous IPSCs (sIPSCs) frequency or amplitude in the substantia nigra pars reticulata (SNpr). An increase in frequency, but not in amplitude, of sIPSCs was only observed when SKF38393 and PDE10A inhibitors were associated to perfusion with higher extracellular K(+). On the other hand, the amplitude of evoked IPSCs (eIPSCs) of the striato-nigral projection to SNpr, was increased in response to co-administration of SKF38393 and papaverine in normal extracellular potassium. Of note, both an increase in sIPSCs frequency and eIPSC amplitude could be obtained either by a robust stimulation of adenylyl cyclase (AC) with forskolin (10 ?M) or by a lower dose of forskolin (1 ?M) associated to PDE inhibition. We next investigated the effects produced by dopamine (DA) depletion in the striatum. Under this condition, SKF38393 alone increased either sIPSCs frequency and eIPSC amplitude. In addition, in the striatum of DA-depleted mice we found reduced PDE10A levels and higher cAMP-dependent phosphorylation in response to D1 receptor stimulation. In accordance with these biochemical data, perfusion with papaverine had no effect on the SKF38393-induced changes of IPSCs in slices of DA-depleted mice. These findings reveal a dynamic interplay between PDE10A activity, level of neuronal network depolarization and degree of dopaminergic tone in the ability of D1 receptors to facilitate the GABAergic transmission to SNpr neurons from the direct nigro-striatal pathway. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'. PMID:23973317

Mango, Dalila; Bonito-Oliva, Alessandra; Ledonne, Ada; Nisticò, Robert; Castelli, Valentina; Giorgi, Mauro; Sancesario, Giuseppe; Fisone, Gilberto; Berretta, Nicola; Mercuri, Nicola Biagio

2013-08-22

61

Effect of acute monoamine depletion on 3,4-methylenedioxymethamphetamine-induced neurotoxicity.  

PubMed

The effect of acute, reversible depletion of either serotonin [5-hydroxytryptamine (5-HT)] or dopamine (DA) on the long-term (7-day) decrease of brain 5-HT content produced after 3,4-methylenedioxymethamphetamine (MDMA) administration was investigated. The tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (alpha-MPT) significantly attenuated the acute increase in DA efflux produced by MDMA in the striatum as measured by in vivo microdialysis. Treatment with alpha-MPT had no effect on MDMA-induced 5-HT release. alpha-MPT treatment blocked the long-term (7-day) depletion of striatal 5-HT content after MDMA administration. The tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) completely blocked the acute increase in the extracellular concentration of 5-HT produced by MDMA. Although PCPA significantly attenuated the increase in DA efflux produced by MDMA, the effect was small in magnitude. More importantly, treatment with PCPA had no effect on MDMA-induced decrease of 5-HT uptake sites in the frontal cortex. These data are suggestive that acute depletion of DA but not 5-HT protects against the long-term neurotoxic effects of MDMA on 5-HT axon terminals. In addition, these data are supportive of the hypothesis that DA plays a major role in the neurotoxic effects of MDMA. PMID:8101380

Brodkin, J; Malyala, A; Nash, J F

1993-07-01

62

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

SciTech Connect

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

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

1987-08-10

63

Identifying the induced depletion of ^166m Ho  

NASA Astrophysics Data System (ADS)

Current nuclear data indicates that incoming photons below 300 keV may allow for an induced depletion of the ^166Ho isomer. Such photons will excite the nucleus of a sample of ^166mHo up to a higher state. From there, the nucleus could decay back to this first metastable state or take a separate decay path down to the ground state. While the first metastable state has a half-life of 1200 years, such an induced depletion would allow the nucleus to decay to its ground state in just fractions of a second. From there, further beta decay occurs on the order of about 24 hours. During the induced depletion cascade, a 136 keV gamma ray will be emitted from a level that has a 185 ?s half-life and is above the initial isomer. A detection system has been designed to detect this unique photon as well as evidence of the 185 ?s half-life; both are signals that the induced depletion has occurred. A cerium-doped lanthanum chloride (LaCl3:Ce) scintillator coupled to a gated photomultiplier tube is used to observe gamma rays from the isomeric sample of ^166Ho. Timing data of the unique photon will be recorded in between bremsstrahlung pulses from an electron linac. First results of this experiment will be discussed.

Detwiler, B. A.; Caldwell, N.; Trees, G. P.; Carroll, J. J.; Pereira, N.; Litz, M.; Merkel, G.; Schumer, J.

2009-10-01

64

Auxin-inducible protein depletion system in fission yeast  

PubMed Central

Background Inducible inactivation of a protein is a powerful approach for analysis of its function within cells. Fission yeast is a useful model for studying the fundamental mechanisms such as chromosome maintenance and cell cycle. However, previously published strategies for protein-depletion are successful only for some proteins in some specific conditions and still do not achieve efficient depletion to cause acute phenotypes such as immediate cell cycle arrest. The aim of this work was to construct a useful and powerful protein-depletion system in Shizosaccaromyces pombe. Results We constructed an auxin-inducible degron (AID) system, which utilizes auxin-dependent poly-ubiquitination of Aux/IAA proteins by SCFTIR1 in plants, in fission yeast. Although expression of a plant F-box protein, TIR1, decreased Mcm4-aid, a component of the MCM complex essential for DNA replication tagged with Aux/IAA peptide, depletion did not result in an evident growth defect. We successfully improved degradation efficiency of Mcm4-aid by fusion of TIR1 with fission yeast Skp1, a conserved F-box-interacting component of SCF (improved-AID system; i-AID), and the cells showed severe defect in growth. The i-AID system induced degradation of Mcm4-aid in the chromatin-bound MCM complex as well as those in soluble fractions. The i-AID system in conjunction with transcription repression (off-AID system), we achieved more efficient depletion of other proteins including Pol1 and Cdc45, causing early S phase arrest. Conclusion Improvement of the AID system allowed us to construct conditional null mutants of S. pombe. We propose that the off-AID system is the powerful method for in vivo protein-depletion in fission yeast.

2011-01-01

65

Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase–saporin impairs attentional function and enhances the effects of guanfacine in the rat  

Microsoft Academic Search

Rationale  Previous data indicate that depletion of cortical noradrenaline (NA) impairs performance of an attentional five-choice serial reaction time task (5CSRT) under certain conditions. This study employed a novel immunotoxin, anti-dopamine-beta hydroylase (D?H)–saporin, to make relatively selective lesions of the noradrenergic projections to the prefrontal cortex (PFC) in rats trained to perform the 5CSRT.Objectives  The aim of this work is to examine

Jean A. Milstein; Olivia Lehmann; David E. H. Theobald; Jeffrey W. Dalley; Trevor W. Robbins

2007-01-01

66

Differential locomotor interactions between dopamine D1\\/D2 receptor agonists and the NMDA antagonist dizocilpine in monoamine-depleted mice  

Microsoft Academic Search

Summary Previous work in our laboratory has shown that the non-competitive N-methyl-D-aspartate antagonist dizocilpine (MK-801) interacts synergistically with the mixed dopamine (DA) receptor agonist apomorphine and the DA D 1 agonist SKF 38393 to promote locomotion in monoamine-depleted mice. The purpose of the present study was to compare the roles of DA D 1 and DA D 2 receptors in

A. Svensson; A. Carlsson; M. L. Carlsson

1992-01-01

67

Dopamine-induced Paroxysmal Supraventricular Tachycardia in an Infant  

Microsoft Academic Search

Dopamine is an effective inotropic agent in the management of circulatory collapse. Ventricular dysrhythmias are reported to occur during dopamine in fusion. The following report describes an infant with circulatory failure who experienced an episode of paroxysmal supraventricular tachycardia while receiving dopamine. Instability or immaturity of the cardiac conduction system during early infancy may contribute to the induction of an

Eli Shahar; Danny Lotan; Zohar Barzilay

1981-01-01

68

Dopamine D1 receptors mediate dopamine-induced duodenal epithelial ion transport in rats.  

PubMed

Dopamine (DA) is synthesized in gastrointestinal epithelial cells and performs important regulatory effects on the duodenal mucosa. However, the underlying mechanism remains largely unknown. The present study investigated the effect of DA on the duodenal epithelial ion transport in rats by means of short-circuit current (ISC), real-time pH titration, enzyme-linked immunosorbent assay, and immunohistochemistry. The results indicate that basolateral, but not apical, application of DA induced a concentration-dependent ISC downward deflection with an apparent IC50 of 5.34 ?mol/L. Basolateral application of dopaminergic receptor D1 (D1) antagonist, SCH-23390, inhibited DA-induced change in ISC (?ISC) in a dose-dependent manner. D1 agonist, SKF38393, mimicked the effect of DA on the ISC. The clear immunoreactivity of D1 subtype D5 (D1b) was at the both apical and basolatoral sides of Brunner's glands and intestinal crypts. Basolateral pretreatment with adenylate cyclase inhibitor, MDL12330A, significantly inhibited DA- and forskolin-induced ?ISC. DA and SKF38393 increased the level of intracellular cyclic adenosine monophosphate (cAMP) from 1.55 ± 0.11 to 2.07 ± 0.11 and 5.91 ± 0.25 pmol/L·mg(-1), respectively. Furthermore, the serosal DA-induced ?ISC was remarkably inhibited by apical administration of K(+) channel blockers, Ba(2+) and tetraethylammonium, but not by Cl(-) channel blockers. Serosal DA and D1 agonist did not affect duodenal HCO3(-) secretion. In conclusion, the present results demonstrate that serosal DA is able to promote rat duodenal epithelial K(+) secretion, not HCO3(-) secretion through D1-mediated and cAMP-dependent pathway. The study provides a new insight in the modulation of DA on the ion transport of duodenal epithelia in rats. PMID:23276732

Feng, Xiao-Yan; Li, Yun; Li, Li-Sheng; Li, Xiao-Feng; Zheng, Li-Fei; Zhang, Xiao-Li; Fan, Rui-Fang; Song, Jin; Hong, Feng; Zhang, Yue; Zhu, Jin-Xia

2012-12-29

69

Demonstration of shape selectivity in depletion-induced colloidal aggregation  

NASA Astrophysics Data System (ADS)

We have developed a set of monodisperse, non-spherical colloids using photolithography in order to elucidate fundamental questions related to the role of shape in defining colloidal phase behaviour and, eventually, to build new microstructured materials. Our goal is to use depletion and DLVO forces to induce specific and directional interactions during the aggregation process of these non-spherical colloids. We will first describe the development and basic characterization of these particles, including index of refraction, zeta potential, polydispersity, and surface roughness. We will then present an initial state diagram of depletion-induced structure, and provide mechanistic insight into the role of specific characteristics of the particles in defining this behaviour. We will finally discuss theoretical calculations of the expected interactions and the possibility of generalizing the results to other colloidal systems.

Badaire, Stephane; Woody, Joseph W.; Cottin-Bizonne, Cecile; Stroock, Abraham D.

2006-03-01

70

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

71

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

Microsoft Academic Search

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

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

2012-01-01

72

Basophil depletion downregulates Schistosoma mansoni egg-induced granuloma formation.  

PubMed

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

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

2013-07-12

73

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

74

Platelet activating factor induces dopamine release in PC-12 cell line  

SciTech Connect

The ability of platelet activating factor (PAF) to stimulate dopamine release and modify calcium homeostasis in PC-12 cell line was studied. PAF-induced dopamine release is related to its molecular form, with only the R-form steric configuration ((R)PAF), but not its S-form or its 2-lyso derivative, effective at being active. In addition, PAF acts at very low concentrations in a dose-dependent manner (0.1-30 nM). Preincubation with PAF receptor antagonists (CV-3988 and BN52021) as well as the specific desensitization of PC-12 cells to (R)PAF abolish the (R)PAF-induced dopamine release. Several lines of evidence suggest that dopamine release is dependent on a (R)PAF-induced calcium influx and efflux modulation. Dopamine release by PC-12 cells challenged with (R)PAF is associated with a rapid {sup 45}Ca influx and efflux and a rise in cytoplasmic calcium concentrations ((Ca{sup 2+}){sub i}) evaluated by using the calcium indicators fura-2 and quin2. At 30 nM (R)PAF, the absence of extracellular calcium inhibits the dopamine release but not the rise of (Ca{sup 2+}){sub i} from the internal stores, suggesting the importance of calcium influx in (R)PAF-induced dopamine release. PAF, which has been reported to be synthesized by stimulated neuronal cells may thus have a physiological modulatory role on cells with neurosecretory properties.

Bussolino, F.; Tessari, F.; Turrini, F.; Braquet, P.; Camussi, G.; Prosdocimi, M.; Bosia, A. (Universita di Torino, Abano Terme (Italy) Institut Henri Beaufour, Le Plessis Robinson (France))

1988-10-01

75

Hemin-induced necroptosis involves glutathione depletion in mouse astrocytes.  

PubMed

Intracerebral hemorrhage (ICH) is a devastating neurological injury associated with significant mortality. Astrocytic inflammation may contribute to the pathogenesis of ICH, although the underlying cellular mechanisms remain unclear. In this study, the hemoglobin oxidation by-product, hemin, concentration dependently induced necroptotic cell death in cortical astrocytes within 5 h of treatment. Hemin-induced cell death was preceded by increased inflammatory gene expression (COX-2, IL-1beta, TNF-alpha, iNOS). Inhibition of the NF-kappaB transcription factor reversed inflammatory gene expression and attenuated cell death after hemin treatment, suggesting a possible role for inflammatory mediators in astrocytic injury. Superoxide production paralleled the increase in iNOS expression, and inhibition of either iNOS (aminoguanidine or iminopiperdine) or superoxide (apocynin) significantly reduced cell death. Similarly, reduced formation of peroxynitrite, the damaging product of nitric oxide and superoxide, significantly reduced hemin injury. Hemin-induced peroxidative injury was associated with a rapid depletion of intracellular glutathione (GSH), culminating in lipid peroxidation and cell death, effects that were reduced by cotreatment with exogenous GSH, N-acetyl-L-cysteine, or the glutathione peroxidase mimetic ebselen. Together, these studies suggest a novel role for GSH depletion in necroptotic astrocyte injury after a hemorrhagic injury and indicate that therapeutic targeting of GSH may exert a beneficial effect after ICH. PMID:18706498

Laird, Melissa D; Wakade, Chandramohan; Alleyne, Cargill H; Dhandapani, Krishnan M

2008-07-16

76

Dopamine-induced programmed cell death in mouse thymocytes  

Microsoft Academic Search

Exposure of mouse thymocytes to dopamine caused apoptosis (programmed cell death). This was manifested by cellular condensation and membrane damage shown by flow cytometry measurements and scanning electron microscopic study. Dopamine also affected thymocytic nuclei and their genomic DNA integrity. Most of the DNA molecules accumulated in a subdiploid peak in flow cytometry analysis, indicating DNA fragmentation to small particles.

Daniel Offen; Ilan Ziv; Svetlana Gorodin; Ari Barzilai; Zvi Malik; Eldad Melamed

1995-01-01

77

Depletion-induced structure and dynamics in bimodal colloidal suspensions.  

PubMed

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. PMID:21635129

Sikorski, M; Sandy, A R; Narayanan, S

2011-05-03

78

Selective Role of Glutathione in Protecting Human Neuronal Cells From Dopamine-induced Apoptosis  

Microsoft Academic Search

The role of glutathione and other antioxidants in dopamine-induced apoptosis has been analyzed in cultures of the human neuronal cell line NMB. Apoptosis, induced by 0.1–0.3 mM dopamine, was blocked by glutathione in a dose- and time-dependent manner. This was observed by monitoring cell morphology, cell viability, and the release of the cytosolic enzyme lactate dehydrogenase into the culture medium.

M GABBAY; M TAUBER; S PORAT; R SIMANTOV

1996-01-01

79

Independent mediation of unconditioned motor behavior by striatal D 1 and D 2 receptors in rats depleted of dopamine as neonates  

Microsoft Academic Search

The effects of systemic administration of DA receptor antagonists suggest that unconditioned motor behavior in rats depleted of DA as neonates continues to be dependent upon dopaminergic transmission, yet the specific contribution of D1 and D2 receptors to these behaviors has been altered. The purpose of the present study was to determine whether these depletion-induced receptor changes are occurring at

J. P. Bruno; E. M. Byrnes; B. J. Johnson

1995-01-01

80

ATP depletion inhibits glucocorticoid-induced thymocyte apoptosis.  

PubMed Central

In quiescent thymocytes, mitochondrial de-energization was not correlated to apoptotic death. In fact, thymocytes treated with oligomycin, a highly specific inhibitor of ATP synthase, alone or with atractyloside to block ATP translocation from the cytoplasm, were alive, even if their mitochondria were depolarized, as revealed by flow cytometry after Rhodamine 123 staining. Furthermore, oligomycin was a powerful inhibitor of apoptosis induced in rat thymocytes by dexamethasone and, to a lesser extent, by the calcium ionophore A23187 and etoposide, but was without effect when apoptosis was induced by staurosporine, and increased cell death in mitogen-treated thymocytes. The inhibition of apoptosis was confirmed by morphological criteria, inhibition of inter-nucleosomal DNA fragmentation and inhibition of the loss of membrane integrity. The anti-apoptotic effect of oligomycin in cells treated with A23187 or etoposide was correlated to the inhibition of protein synthesis, while inhibition of apoptosis induced by dexamethasone, already evident at an oligomycin concentration of 10 ng/ml, was instead strictly correlated to the effect exerted on the cellular ATP level. Thymocyte apoptosis triggered by dexamethasone was blocked or delayed by inhibitors of respiratory-chain uncouplers, inhibitors of ATP synthase and antioxidants: a lasting protection from dexamethasone-induced apoptosis was always correlated to a drastic and rapid reduction in ATP level (31-35% of control), while a delay in the death process was characterized by a moderate decrease in ATP (73-82% of control). Oligomycin inhibited the specific binding of radioactive corticosteroid to thymocyte nuclei, confirming the inhibitory effect of ATP depletion on glucocorticoid binding and suggesting that ATP depletion is a common mediator of the anti-apoptotic action of different effectors in glucocorticoid-induced apoptosis. In conclusion, the reported data indicate that ATP may act as a cellular modulator of some forms of apoptosis, depending on the death trigger, and that in quiescent cells the de-energization of mitochondria is not necessarily linked to apoptosis.

Stefanelli, C; Bonavita, F; Stanic', I; Farruggia, G; Falcieri, E; Robuffo, I; Pignatti, C; Muscari, C; Rossoni, C; Guarnieri, C; Caldarera, C M

1997-01-01

81

Disulfiram stimulates dopamine release from noradrenergic terminals and potentiates cocaine-induced dopamine release in the prefrontal cortex  

Microsoft Academic Search

Rationale  Disulfiram efficacy in treatment of cocaine addiction is attributed to the inhibition of dopamine-?-hydroxylase and reduction\\u000a in brain noradrenaline (NA)\\/dopamine (DA) ratio.\\u000a \\u000a \\u000a \\u000a \\u000a Objectives  Using microdialysis, we investigated if disulfiram causes DA release from noradrenergic terminals and modifies cocaine-induced\\u000a DA release.\\u000a \\u000a \\u000a \\u000a \\u000a Results  Disulfiram reduced extracellular NA in the medial prefrontal (mPF) cortex, occipital cortex, accumbens and caudate nuclei,\\u000a while it markedly increased DA

Paola Devoto; Giovanna Flore; Pierluigi Saba; Roberto Cadeddu; Gian Luigi Gessa

82

Quantification of Depletion-Induced Adhesion of Red Blood Cells  

NASA Astrophysics Data System (ADS)

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

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

2013-01-01

83

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

PubMed

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

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

2010-09-06

84

Zinc induces depletion and aggregation of endogenous TDP-43.  

PubMed

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

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

2010-02-04

85

Dopamine dynamics associated with, and resulting from, schedule-induced alcohol self-administration: Analyses in dopamine transporter knockout mice  

PubMed Central

Preclinical and clinical evidence suggest an association between alcoholism and the primary regulator of extracellular dopamine concentrations, the dopamine transporter (DAT). However, the nature of this association is unclear. We determined if ten days of voluntary alcohol self-administration followed by withdrawal could directly alter DAT function, or if genetically-mediated changes in DAT function and/or availability could influence vulnerability to alcohol abuse. Heterozygous (DAT+/-) and homozygous mutant (DAT-/-) and wildtype (DAT+/+) mice were allowed to consume 5% alcohol in a schedule-induced polydipsia (SIP) task. In vivo fixed potential amperometry in anesthetized mice was used to (1) identify functional characteristics of mesoaccumbens dopamine neurons related to genotype, including dopamine autoreceptor (DAR) sensitivity, DAT efficiency, and DAT capacity, (2) determine if any of these characteristics correlated with alcohol drinking observed in DAT+/+ and DAT+/- animals, and (3) determine if SIP-alcohol self-administration altered DAR sensitivity, DAT efficiency, and DAT capacity by comparing these characteristics in wildtype (DAT+/+) mice that were SIP-alcohol naïve, with those that had undergone SIP-alcohol testing. DAT-/- mice consumed significantly less alcohol during testing and this behavioral difference was related to significant differences in DAR sensitivity, DAT efficiency, and DAT capacity. These functional characteristics were correlated to varying degrees with g/kg alcohol consumption in DAT+/+ and DAT+/- mice. DAR sensitivity was consistently reduced and DAT efficiency was enhanced in SIP-alcohol experienced DAT+/+ mice in comparison to naïve animals. These results indicate that DAR sensitivity is reduced by SIP-alcohol consumption and that DAT efficiency is modified by genotype as well as SIP-alcohol exposure. DAT capacity appeared to be strictly associated with SIP-alcohol consumption.

Mittleman, Guy; Call, Stanford B.; Cockroft, Jody L.; Goldowitz, Dan; Matthews, Douglas B.; Blaha, Charles D.

2011-01-01

86

Different neural mechanisms underlie dizocilpine maleate- and dopamine agonist-induced locomotor activity  

Microsoft Academic Search

This study evaluated and compared the role of mesoaccumbens dopamine and the ventral pallidal region in the locomotor stimulatory action of the non-competitive N-methyl-d-aspartate antagonist dizocilpine maleate and dopamine agonists. Intra-accumbens injections of both amphetamine (1, 5 and 25nmol) and dizocilpine maleate (1, 5, 25 and 50nmol) induced a dose-dependent increase in locomotor activity. The N-methyl-d-aspartate antagonist was somewhat less

A Mele; D. N Thomas; A Pert

1997-01-01

87

Dopamine receptor sensitivity after chronic dopamine agonists  

Microsoft Academic Search

Several previous reports have demonstrated that chronic administration of both directly and indirectly acting dopamine agonists produces a supersensitive behavioral response to challenge doses of dopamine agonists when compared to the responses induced by acute administration of these drugs. That is, a given dose of a dopamine agonist will produce a greater response after chronic dopamine agonist treatment than is

William H. Riffee; Richard E. Wilcox; Dana M. Vaughn; Robert V. Smith

1982-01-01

88

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, João

2011-06-25

89

Increased dopamine tone during meditation-induced change of consciousness.  

PubMed

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

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

2002-04-01

90

Caffeine Expectancies but Not Caffeine Reduce Depletion-Induced Aggression  

Microsoft Academic Search

Caffeine is the most widely consumed central nervous system stimulant in the world, yet little is known about its effects on aggressive behavior. Individuals often consume caffeine to increase energy and ward off mental depletion. Because mental depletion increases aggression when people are provoked, caffeine might reduce aggression by ameliorating the negative effects of depletion. In 2 experiments, participants consumed

Thomas F. Denson; Mandi Jacobson; William von Hippel; Richard I. Kemp; Tinnie Mak

2012-01-01

91

Prefrontal cortical D1 dopamine receptors modulate subcortical D2 dopamine receptor-mediated stress responsiveness.  

PubMed

Increased responsiveness to stress plays an important role in the manifestation of schizophrenia symptoms. Evidence indicates that the prefrontal cortex (PFC), and dopamine neurotransmission in the PFC in particular, is involved in the modulation of stress responsiveness. Decreased dopaminergic activity and loss of dopamine fibres have been reported in PFC in schizophrenia patients. Consequently, it was hypothesized that depletion of dopamine in PFC may facilitate increased stress responsiveness. Adult Sprague-Dawley rats received injections of 6-hydroxydopamine or saline bilaterally into the medial PFC (mPFC) following desipramine pretreatment to selectively deplete dopaminergic fibres. Following a 3-wk recovery period, the lesioned and control rats received injections of a D1 or D2 dopamine receptor agonist or vehicle into the mPFC and were immediately subjected to forced swimming as a stressor. Results showed that frequency of locomotion and rearing, behavioural measures indicative of increased dopaminergic activity in the nucleus accumbens (NAc), were significantly increased following stress in prefrontal cortical dopamine-depleted rats. This effect was significantly ameliorated by infusions of a D1 dopamine receptor agonist directly into the mPFC in a dose-dependent manner but not by infusion of a D2 dopamine receptor agonist. In addition, stress-induced behavioural changes in prefrontal cortical dopamine-depleted rats were significantly reduced following selective discrete infusions of a D2 dopamine receptor antagonist into the NAc shell. The results suggest that dopaminergic transmission via D1 receptors in the mPFC modulates D2 dopamine receptor-mediated stress responsiveness in the NAc, a feature that may be disrupted in schizophrenia patients. PMID:19275776

Scornaiencki, Rachel; Cantrup, Robert; Rushlow, Walter J; Rajakumar, Nagalingam

2009-03-11

92

Fighting: Preferential Lowering of Norepinephrine and Dopamine in the Brainstem, Concomitant with a Depletion of Epinephrine from the Adrenal Medulla.  

National Technical Information Service (NTIS)

Male white Swiss mice that had been made agressive by long-term isolation were placed together in groups of four and allowed to fight for 5, 45, and 150 min. Norepinephrine and dopamine were lowered in the brainstem and, at the longest period of time, wer...

B. L. Welch A. S. Welch

1969-01-01

93

Increased baseline occupancy of D2 receptors by dopamine in schizophrenia  

PubMed Central

The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic transmission at the D2 receptor. We measured in vivo occupancy of striatal D2 receptors by dopamine in 18 untreated patients with schizophrenia and 18 matched controls, by comparing D2 receptor availability before and during pharmacologically induced acute dopamine depletion. Acute depletion of intrasynaptic dopamine resulted in a larger increase in D2 receptor availability in patients with schizophrenia (19% ± 11%) compared with control subjects (9% ± 7%, P = 0.003). The increased occupancy of D2 receptors by dopamine occurred both in first-episode neuroleptic-naive patients and in previously treated chronic patients experiencing an episode of illness exacerbation. In addition, elevated synaptic dopamine was predictive of good treatment response of positive symptoms to antipsychotic drugs. This finding provides direct evidence of increased stimulation of D2 receptors by dopamine in schizophrenia, consistent with increased phasic activity of dopaminergic neurons.

Abi-Dargham, Anissa; Rodenhiser, Janine; Printz, David; Zea-Ponce, Yolanda; Gil, Roberto; Kegeles, Lawrence S.; Weiss, Richard; Cooper, Thomas B.; Mann, J. John; Van Heertum, Ronald L.; Gorman, Jack M.; Laruelle, Marc

2000-01-01

94

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

95

Depletion-induced biaxial nematic states of boardlike particles.  

PubMed

With the aim of investigating the stability conditions of biaxial nematic liquid crystals, we study the effect of adding a non-adsorbing ideal depletant on the phase behavior of colloidal hard boardlike particles. We take into account the presence of the depletant by introducing an effective depletion attraction between a pair of boardlike particles. At fixed depletant fugacity, the stable liquid-crystal phase is determined through a mean-field theory with restricted orientations. Interestingly, we predict that for slightly elongated boardlike particles a critical depletant density exists, where the system undergoes a direct transition from an isotropic liquid to a biaxial nematic phase. As a consequence, by tuning the depletant density, an easy experimental control parameter, one can stabilize states of high biaxial nematic order even when these states are unstable for pure systems of boardlike particles. PMID:22739023

Belli, S; Dijkstra, M; van Roij, R

2012-06-27

96

Depletion-induced biaxial nematic states of boardlike particles  

NASA Astrophysics Data System (ADS)

With the aim of investigating the stability conditions of biaxial nematic liquid crystals, we study the effect of adding a non-adsorbing ideal depletant on the phase behavior of colloidal hard boardlike particles. We take into account the presence of the depletant by introducing an effective depletion attraction between a pair of boardlike particles. At fixed depletant fugacity, the stable liquid-crystal phase is determined through a mean-field theory with restricted orientations. Interestingly, we predict that for slightly elongated boardlike particles a critical depletant density exists, where the system undergoes a direct transition from an isotropic liquid to a biaxial nematic phase. As a consequence, by tuning the depletant density, an easy experimental control parameter, one can stabilize states of high biaxial nematic order even when these states are unstable for pure systems of boardlike particles.

Belli, S.; Dijkstra, M.; van Roij, R.

2012-07-01

97

Increased dopamine tone during meditation-induced change of consciousness  

Microsoft Academic Search

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

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

2002-01-01

98

Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost\\/benefit task  

Microsoft Academic Search

This experiment was conducted to study the role of nucleus accumbens dopamine in the performance of a novel T-maze cost\\/benefit procedure. Rats were trained on a T-maze task for food reinforcement. Under one of the test conditions, one arm of the maze contained a high reinforcement density (4 × 45 mg Bioserve pellets) and the other arm contained a low

M. S. Cousins; A. Atherton; L. Turner; J. D. Salamone

1996-01-01

99

Enhancement of delayed release of dopamine in the amygdala induced by conditioned fear stress in methamphetamine-sensitized rats  

Microsoft Academic Search

Behavior during conditioned fear stress, a form of psychological stress, and the release of dopamine in the amygdala were measured over time using methamphetamine-sensitized rats, which are considered to be a model of hypersensitivity and vulnerability to emotional stress associated with stimulant-induced psychosis and schizophrenia. Dopamine release in the amygdala showed a delayed increase following completion of freezing behavior induced

Takaharu Suzuki; Jun Ishigooka; Shigeru Watanabe; Hitoshi Miyaoka

2002-01-01

100

Response of striosomal opioid signaling to dopamine depletion in 6-hydroxydopamine-lesioned rat model of Parkinson's disease: a potential compensatory role  

PubMed Central

The opioid peptide receptors consist of three major subclasses, namely, ?, ?, and ? (MOR, DOR, and KOR, respectively). They are involved in the regulation of striatal dopamine functions, and increased opioid transmissions are thought to play a compensatory role in altered functions of the basal ganglia in Parkinson's disease (PD). In this study, we used an immunohistochemistry with tyramide signal amplification (TSA) protocols to determine the distributional patterns of opioid receptors in the striosome-matrix systems of the rat striatum. As a most striking feature of striatal opioid anatomy, MORs are highly enriched in the striosomes and subcallosal streak. We also found that DORs are localized in a mosaic pattern in the dorsal striatum (caudate-putamen), with heightened labeling for DOR in the striosomes relative to the matrix compartment. In the 6-hydroxydopamine-lesioned rat model of PD, lesions of the nigrostriatal pathways caused a significant reduction of striatal labeling for both the MOR and DOR in the striosomes, but not in the matrix compartment. Our results suggest that the activities of the striosome and matrix compartments are differentially regulated by the opioid signals involving the MORs and DORs, and that the striosomes may be more responsive to opioid peptides (e.g., enkephalin) than the matrix compartment. Based on a model in which the striosome compartment regulates the striatal activity, we propose a potent compensatory role of striosomal opioid signaling under the conditions of the striatal dopamine depletion that occurs in PD.

Koizumi, Hidetaka; Morigaki, Ryoma; Okita, Shinya; Nagahiro, Shinji; Kaji, Ryuji; Nakagawa, Masanori; Goto, Satoshi

2013-01-01

101

Depleted uranium induces neoplastic transformation in human lung epithelial cells.  

PubMed

Depleted uranium (DU) is commonly used in military armor and munitions, and thus, exposure of soldiers and noncombatants is frequent and widespread. Previous studies have shown that DU has both chemical and radiological toxicity and that the primary route of exposure of DU to humans is through inhalation and ingestion. However, there is limited research information on the potential carcinogenicity of DU in human bronchial cells. Accordingly, we determined the neoplastic transforming ability of particulate DU to human bronchial epithelial cells (BEP2D). We observed the loss of contact inhibition and anchorage independent growth in cells exposed to DU after 24 h. We also characterized these DU-induced transformed cell lines and found that 40% of the cell lines exhibit alterations in plating efficiency and no significant changes in the cytotoxic response to DU. Cytogenetic analyses showed that 53% of the DU-transformed cell lines possess a hypodiploid phenotype. These data indicate that human bronchial cells are transformed by DU and exhibit significant chromosome instability consistent with a neoplastic phenotype. PMID:20000475

Xie, Hong; LaCerte, Carolyne; Thompson, W Douglas; Wise, John Pierce

2010-02-15

102

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

PubMed Central

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

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

2010-01-01

103

Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity  

Microsoft Academic Search

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

Ikuko Miyazaki; Masato Asanuma

2009-01-01

104

MDMA induced dopamine release in vivo: role of endogenous serotonin  

Microsoft Academic Search

Summary Acting as a substrate at the serotonin (5-HT) transporter, (+)-MDMA (3,4-methylenedioxymethamphetamine), is a potent releaser of 5-HT and causes toxicity to 5-HT neurons after repeated exposure. (+)-MDMA also releases dopamine (DA), although with less potency. Since we have shown previously that the intrastriatal application of 5-HT facilitates DA release, it was hypothesized that increased release of striatal 5-HT after

S. Koch; M. P. Galloway

1997-01-01

105

Dopamine Selectively Sensitizes Dopaminergic Neurons to Rotenone-Induced Apoptosis  

Microsoft Academic Search

Among various types of neurons affected in Parkinson’s disease, dopamine (DA) neurons of the substantia nigra undergo the\\u000a most pronounced degeneration. Products of DA oxidation and consequent cellular damage have been hypothesized to contribute\\u000a to neuronal death. To examine whether elevated intracellular DA will selectively predispose the dopaminergic subpopulation\\u000a of nigral neurons to damage by an oxidative insult, we first

Ferogh A. Ahmadi; Tom N. Grammatopoulos; Andy M. Poczobutt; Susan M. Jones; Laurence D. Snell; Mita Das; W. Michael Zawada

2008-01-01

106

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

107

Methamphetamine-induced dopamine-independent alterations in striatal gene expression in the 6-hydroxydopamine hemiparkinsonian rats.  

PubMed

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. PMID:21179447

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

2010-12-13

108

Polymer-induced depletion attraction between nanoparticles in confined conditions  

NASA Astrophysics Data System (ADS)

We studied the polymer-mediated depletion pair interaction between nanoparticles and/or proteins in polymer solutions in confined conditions. The self-consistent field (SCF) theory for a polymer - nanoparticles systems in confined systems is solved numerically by using the pseudo-spectral method. We have analyzed the behavior of non-adsorbing particles in a polymer solution near a non-adsorbing wall for which the polymer mediated particle-particle and particle-wall interaction in such systems are known to be a depletion attraction. Our main results for such system are the following: polymer depletion from the wall causes the polymer density to decrease near the wall and reduces the particle-particle depletion attraction near the wall. In a similar manner, the particle-wall attraction is also screened due to presence of another particle. Our results surprisingly suggested a simple scaling to rationalize the wall-mediated interparticle potentials. Specifically, the wall-mediated depletion interactions were shown to be semi-quantitatively captured by the depletion interaction between two particles in an unconfined polymer solution at a density corresponding to the density of the polymer solution at midpoint between the two particles. These results suggest that the phase behavior of

Pryamitsyn, Victor; Ganesan, Venkat

2013-03-01

109

D2 dopamine receptor antagonist raclopride induces non-canonical autophagy in cardiac myocytes.  

PubMed

Cell death by autophagy is an important means of maintaining cellular homeostasis in adult cardiac myocytes. Autophagy was previously shown to exert a cardioprotective effect, suggesting that modulation of autophagy pathways is a potential therapeutic strategy in the treatment of heart disease. Although dopamine is known to induce autophagy in neuroblastoma cells, the underlying mechanism and the types of dopamine receptors involved in this process remain unclear. In this study, we used various dopamine receptor antagonists and agonists to identify the specific dopamine receptor that mediates induction of autophagy. We evaluated autophagy induction by the expression of autophagy markers in neonatal rat ventricular cardiac myocytes. We evaluated intracellular calcium levels using Fluo-3/AM and demonstrated autophagy-induced morphological changes in cardiac myocytes using electron microscopy. We also examined the pathway for dopamine-induced autophagy using RNAi-mediated gene knockdown. Raclopride, the well-documented D2 receptor antagonist, significantly upregulated autophagy in cardiac myocytes via an mTOR-independent pathway. There was no difference in intracellular calcium levels between raclopride-treated cells and untreated cells. siRNA-mediated knockdown of Rab9 resulted in decreased expression of autophagy markers in raclopride-treated cells. Interestingly, siRNA-mediated knockdown of Atg7 resulted in a significant increase in Rab9 levels in raclopride-treated cells, suggesting that blocking the classical autophagy pathway results in activation of an alternative pathway. Our study suggests that (1) the D2 dopamine receptor plays a role in autophagy and (2) raclopride mediated a non-canonical autophagy pathway in cardiac myocytes via Rab9. PMID:22886761

Yan, Hao; Li, Wen-Lin; Xu, Jian-Jun; Zhu, Shu-Qiang; Long, Xiang; Che, Jian-Peng

2013-01-01

110

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

Microsoft Academic Search

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

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

1998-01-01

111

Chronic levodopa impairs the recovery of dopamine agonist-induced rotational behavior following neural grafting  

Microsoft Academic Search

The effect of chronic levodopa treatment on the function of embryonic mesencephalic tissue grafts was assessed in rats by monitoring rotational behavior elicited by dopamine (DA) agonists before and after neural grafting. Rats were given unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway and baseline measures of rotational behavior induced by D1 receptor stimulation, D2 receptor stimulation, or amphetamine were

D. M. Yurek; K. Steece-Collier; T. J. Collier; J. R. Sladek

1991-01-01

112

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

Microsoft Academic Search

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

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

2009-01-01

113

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

114

Energy-dependent UV light-induced disruption of (-)sulpiride antagonism of dopamine.  

PubMed

The dopamine D2 receptor antagonist sulpiride decreases the spontaneous locomotor activity of Planaria in an enantiomeric-selective and dose-dependent manner. We now report that (-)sulpiride (0.1 microM)-induced decrease of planarian locomotor activity is significantly (P<0.05) attenuated by low-energy (366 nm) ultraviolet (UV) light and to a greater extent by high-energy (254 nm) UV light. The phenomenon offers a novel approach for studying dopamine D2 receptor transduction processes in a simple in vivo model. PMID:11040357

Raffa, R B; Valdez, J M; Holland, L J; Schulingkamp, R J

2000-10-20

115

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

PubMed Central

AIMS—To compare changes in global haemodynamics as well as anterior cerebral and superior mesenteric artery perfusion after dopamine treatment.?METHODS—Anterior 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.?RESULTS—Despite a lower dopamine infusion rate, the blood pressure increase (mm Hg) in group 2 [?=13(1); mean(SE)] exceeded that in group 1 [?=8(1)], while systemic vascular resistance (mm Hg/l/min/kg) rose in group 2 [?=106 (37)], but was unchanged in group 1 [?=9 (6)]. Anterior cerebral artery blood velocity and resistance were unaffected by dopamine. However, compared with unchanged values in group 1, superior mesenteric artery blood velocity fell by 14.7(4.8) cm/s and resistance increased by 4.1(0.7) mm Hg/cm in group 2.?CONCLUSIONS—These results suggest that, in a portion of hypotensive preterm neonates, the increase in blood pressure induced by dopamine is related to a predominant vasoconstrictor action and is associated with a fall in bowel perfusion.??

Zhang, J; Penny, D; Kim, N; Yu, V; Smolich, J

1999-01-01

116

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

SciTech Connect

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

Saleh, M.I.M.

1988-01-01

117

Influence of idazoxan on the dopamine D2 receptor agonist-induced behavioural effects in rats.  

PubMed

The behavioural effects in rats of the dopamine D2 receptor agonists, lisuride, B-HT 920 and SND 919, were variously influenced by pre-treatment with the selective alpha 2-adrenoceptor antagonist, idazoxan (2 mg/kg), depending on the nature of the effect in question and the doses of agonist employed. The influence of idazoxan on drug-induced stretching-yawning, penile erection, sedation, stereotyped behaviour, aggressiveness and mounting is described and tentatively interpreted in neurochemical terms, account being taken of the activity of respective alpha 2-adrenoceptor antagonist and dopamine receptor agonists used, at alpha 2-adrenoceptors and at different dopamine D2 receptor subtypes, pre- and postsynaptically located. PMID:7907024

Ferrari, F; Giuliani, D

1993-11-30

118

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

Microsoft Academic Search

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

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

2004-01-01

119

Creaming of emulsions: the role of depletion forces induced by surfactant  

Microsoft Academic Search

We show that excess surfactant, or salt, in the bulk phase of an oil in water ionic emulsion has strong consequences on the thermodynamical behavior of the dispersion. Static light scattering experiments have been performed to investigate the attractive interaction induced by micelles according to a depletion mechanism. This interaction can be largely reduced by adding salt. This depletion interaction

J. Bibette; D. Roux; B. Pouligny

1992-01-01

120

Antipsychotic drugs rapidly induce dopamine neuron depolarization block in a developmental rat model of schizophrenia  

PubMed Central

Repeated administration of antipsychotic drugs to normal rats has been shown to induce a state of dopamine neuron inactivation known as depolarization block, which correlates with the ability of the drugs to exhibit antipsychotic efficacy and extrapyramidal side-effects in schizophrenia patients. Nonetheless, in normal rats depolarization block requires weeks of antipsychotic drug administration, whereas schizophrenia patients exhibit initial effects soon after initiating antipsychotic drug treatment. We now report that, in a developmental disruption rat model of schizophrenia (methyl-azoxymethanol acetate (20 mg/kg i.p.) injected into G17 pregnant female rats, with offspring tested as adults), the extant hyperdopaminergic state combines with the excitatory actions of a first (haloperidol; 0.6 mg/kg, i.p.)- and second (sertindole; 2.5 mg/kg, i.p.)-generation antipsychotic drug to rapidly induce depolarization block in ventral tegmental area dopamine neurons. Acute injection of either antipsychotic drug induced an immediate reduction in the number of spontaneously active dopamine neurons (cells per electrode track; termed population activity). Repeated administration of either antipsychotic drug for 1 day, 3 days, 7 days, 15 days, and 21 days continued to reduce dopamine neuron population activity. Both acute and repeated effects on population activity were reversed by acute apomorphine injections, which is consistent with the reversal of dopamine neuron depolarization block. Although this action may account for the effects of D2 antagonist drugs on alleviating psychosis and the lack of development of tolerance in humans, the drugs appear to do so by inducing an offsetting deficit rather than attacking the primary pathology present in schizophrenia.

Valenti, Ornella; Cifelli, Pierangelo; Gill, Kathryn M.; Grace, Anthony A.

2011-01-01

121

Dopamine agonist cabergoline inhibits levodopa-induced caspase activation in 6-OHDA-lesioned mice  

Microsoft Academic Search

Levodopa therapy is the gold standard for symptomatic treatment of Parkinson's disease (PD), but levodopa and\\/or dopamine (DA)-induced neurotoxicity have been reported in both in vitro and in vivo experimental studies. To clarify the beneficial effects of combining DA agonists with levodopa in PD, the present study examines the effects of cabergoline, a DA agonist, on the levodopa-induced abnormal increase

Ken-ichi Tanaka; Norio Ogawa

2005-01-01

122

Chemical carcinogens and antigens induce immune suppression via Langerhans' cell depletion.  

PubMed Central

The ability of the chemical carcinogen dimethylbenz(a)anthracene (DMBA) to deplete Langerhans' cells (LC) from murine skin is crucial to the development of antigen-specific suppression. This depletion is a consequence of the LC recognizing the DMBA as antigenic and migrating to the draining lymph nodes to attempt to elicit T-cell activation. This depletion also occurred following exposure to high doses of the contact sensitizers 2,4-dinitrofluorobenzene (DNFB), 2,4,6-trinitrochlorobenzene (TNCB) and fluorescein isothiocyanate (FITC). However, LC depletion was not significant at lower doses, even though these doses were sufficient to induce strong contact sensitivity responses. Application of the contact sensitizer, DNFB, through skin depleted of LC (by pretreatment with either the carcinogen DMBA or the antigen TNCB) failed to induce contact sensitivity. This immune non-responsiveness was antigen specific, and could be transferred by spleen cells to naive mice, which were unable to respond to DNFB. Mouse skin treated with doses of TNCB, that did not cause LC depletion but still induced a normal contact hypersensitivity, retained its ability to initiate a normal immune response to DNFB. Together these findings demonstrate that carcinogens share some properties with antigens as they both cause LC depletion and interact with the immune system. Furthermore, it is this LC depletion, rather than carcinogen treatment, that is a critical factor which leaves the skin immunologically compromised and favours the induction of antigen-specific suppression.

Woods, G M; Qu, M; Ragg, S J; Muller, H K

1996-01-01

123

Noradrenergic inhibition of midbrain dopamine neurons.  

PubMed

Receptors that couple to phosphoinositide hydrolysis, which include metabotropic glutamate receptors (mGluRs) and muscarinic receptors, are known to either activate or inhibit the activity of dopamine cells depending on the pattern of receptor activation. Transient activation of alpha1 adrenoceptors with norepinephrine (NE) resulted in an outward current in midbrain dopamine neurons recorded in brain slices. The NE-mediated outward current was induced by activation of a potassium conductance through release of calcium from intracellular stores. Unlike the mGluR-mediated outward current, the outward current induced by alpha1 adrenoceptors often consisted of multiple peaks. Activation of alpha1 adrenoceptors also induced a wave of calcium release that spread through the soma and proximal dendrites without a decline in amplitude or rate of propagation and therefore differed qualitatively from that induced by mGluRs. Finally, the alpha1 adrenoceptor-activated outward current was more sensitive to the calcium store-depleting agents ryanodine and caffeine. Thus, although both alpha1 adrenoceptors and mGluRs mobilize calcium from intracellular stores, the mechanisms and pools of calcium differ. The results suggest that noradrenergic innervation of dopamine cells can directly inhibit the activity of dopamine cells. Psychostimulants, such as amphetamine, will therefore have a direct effect on the firing pattern of dopamine neurons through a combination of actions on dopamine and alpha1 adrenoceptor activation. PMID:15140928

Paladini, Carlos A; Williams, John T

2004-05-12

124

Dopamine D2-like receptors and amino acid-induced glomerular hyperfiltration in humans  

PubMed Central

Aims In rodents, blockade of dopamine D2-like receptors abolishes both the physiological increase in glomerular filtration rate (GFR) induced by amino acids and the pathological hyperfiltration in experimental diabetes mellitus. This study addressed the contribution of dopamine D2-like receptors to changes in renal haemodynamics after amino acid infusion in humans. Methods Twelve healthy volunteers participated in this double-blind, randomized, cross-over study. GFR and renal blood flow (RPF) were assessed by renal clearance of inulin and p-aminohippuric acid (PAH), respectively. Following infusion of 0.45% saline at baseline, an electrolyte-balanced solution of mixed amino acids (10%) was infused. Prior to the experiments, the subjects received orally either placebo, or sulpiride (10 mg kg?1), a centrally and peripherally acting D2-like receptor antagonist, or domperidone (1 mg kg?1) which affects only peripheral D2-like receptors. Results In the placebo series, amino acid infusion significantly increased GFR and RPF by up to 15.8 ± 5.3% and 14.4 ± 6.1%, respectively, while mean blood pressure and heart rate remained unchanged. Pretreatment with domperidone only marginally altered the renal response to amino acids (maximal increase by 13.2 ± 5.6 and 11.9 ± 4.0% in GFR and RPF, respectively), while sulpiride completely abolished the renal haemodynamic changes induced by amino acids. Total and fractional urinary sodium excretion as well as urinary osmolality were similar at baseline and increased in response to amino acids, to the same extent, in all series. No changes in renal dopamine excretion occurred. Conclusion The results indicate that in man dopamine D2-like receptors are involved in the renal haemodynamic response to amino acid infusion. Whether dopamine D2-like receptor blockade diminishes glomerular hyperfiltration in pathological states requires clinical investigations.

Luippold, Gerd; Schneider, Swetlana; Stefanescu, Andreea; Benohr, Peter; Muhlbauer, Bernd

2001-01-01

125

Copper dopamine complex induces mitochondrial autophagy preceding caspase-independent apoptotic cell death.  

PubMed

Parkinsonism is one of the major neurological symptoms in Wilson disease, and young workers who worked in the copper smelting industry also developed Parkinsonism. We have reported the specific neurotoxic action of copper dopamine complex in neurons with dopamine uptake. Copper dopamine complex (100 microm) induces cell death in RCSN-3 cells by disrupting the cellular redox state, as demonstrated by a 1.9-fold increase in oxidized glutathione levels and a 56% cell death inhibition in the presence of 500 microm ascorbic acid; disruption of mitochondrial membrane potential with a spherical shape and well preserved morphology determined by transmission electron microscopy; inhibition (72%, p < 0.001) of phosphatidylserine externalization with 5 microm cyclosporine A; lack of caspase-3 activation; formation of autophagic vacuoles containing mitochondria after 2 h; transfection of cells with green fluorescent protein-light chain 3 plasmid showing that 68% of cells presented autophagosome vacuoles; colocalization of positive staining for green fluorescent protein-light chain 3 and Rhod-2AM, a selective indicator of mitochondrial calcium; and DNA laddering after 12-h incubation. These results suggest that the copper dopamine complex induces mitochondrial autophagy followed by caspase-3-independent apoptotic cell death. However, a different cell death mechanism was observed when 100 microm copper dopamine complex was incubated in the presence of 100 microm dicoumarol, an inhibitor of NAD(P)H quinone:oxidoreductase (EC 1.6.99.2, also known as DT-diaphorase and NQ01), because a more extensive and rapid cell death was observed. In addition, cyclosporine A had no effect on phosphatidylserine externalization, significant portions of compact chromatin were observed within a vacuolated nuclear membrane, DNA laddering was less pronounced, the mitochondria morphology was more affected, and the number of cells with autophagic vacuoles was a near 4-fold less. PMID:19265190

Paris, Irmgard; Perez-Pastene, Carolina; Couve, Eduardo; Caviedes, Pablo; Ledoux, Susan; Segura-Aguilar, Juan

2009-03-05

126

Epigenetic dysregulation of the dopamine system in diet-induced obesity  

PubMed Central

Chronic intake of high fat diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to high fat 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 prefrontal 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 expression in dopamine-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 versus 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 chronic intake of high fat diet with altered dopamine-related gene expression, and this response varies by brain region and DNA sequence.

Vucetic, Zivjena; Carlin, JesseLea; Totoki, Kathy; Reyes, Teresa M.

2012-01-01

127

Intra-accumbens infusion of D 3 receptor agonists reduces spontaneous and dopamine-induced locomotion  

Microsoft Academic Search

The present study investigated whether PD 128907 and 7-OH-DPAT, described as preferential dopamine (DA) D3 receptor agonists, produce hypolocomotion by acting at postsynaptic dopaminergic receptors within the nucleus accumbens. Bilateral infusion of PD 128907 (1.5 and 3 ?g\\/0.5 ?l) induced a dose-dependent hypolocomotion, whereas its enantiomer, PD 128908, was inactive. Local infusion of 7-OH-DPAT and the preferential DA autoreceptor agonist,

Abdel-Mouttalib Ouagazzal; Ian Creese

2000-01-01

128

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

129

Ontogeny of dopamine agonist-induced sensitization: role of NMDA receptors  

Microsoft Academic Search

In contrast to adults, preweanling rats exhibit behavioral sensitization for only a few days after cessation of dopamine\\u000a (DA) agonist treatment. The reasons for this ontogenetic difference are uncertain, but maturational changes in the N-methyl-d-aspartate (NMDA) receptor may be responsible, since stimulation of these receptors is necessary for the development of DA\\u000a agonist-induced sensitization in adult rats. The purpose of

M. A. Duke; Jason O’Neal; S. A. McDougall

1997-01-01

130

Energy-dependent UV light-induced disruption of (?)sulpiride antagonism of dopamine  

Microsoft Academic Search

The dopamine D2 receptor antagonist sulpiride decreases the spontaneous locomotor activity of Planaria in an enantiomeric-selective and dose-dependent manner. We now report that (?)sulpiride (0.1 ?M)-induced decrease of planarian locomotor activity is significantly (P<0.05) attenuated by low-energy (366 nm) ultraviolet (UV) light and to a greater extent by high-energy (254 nm) UV light. The phenomenon offers a novel approach for

Robert B Raffa; Joseph M Valdez; Lauren J Holland; Robert J Schulingkamp

2000-01-01

131

Cytokine-induced conversion of mesencephalic-derived progenitor cells into dopamine neurons  

Microsoft Academic Search

We have previously shown that a combination of the cytokines interleukin (IL)-1, IL-11, leukemia inhibitory factor (LIF), and glial cell line-derived neurotrophic factor (GDNF) can convert rat fetal (E14.5) mesencephalic progenitor cells into tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in vitro. The experiments described here characterize the mesencephalic progenitor cells and their cytokine-induced conversion into dopamine (DA) neurons. For all experiments,

Elizabeth D. Potter; Zao Dung Ling; Paul M. Carvey

1999-01-01

132

Changes on D2-like receptor induced Gi protein activation and hippocampal dopamine release in kindled rats.  

PubMed

The present study aimed to characterize dopamine release in the hippocampus and D2-like receptor-induced Gi protein activation in several brain areas of fully kindled rats. During the interictal period, kindled rats showed lower extracellular levels of dopamine when compared with those obtained in the control group under basal conditions, a situation that was not modified when an afterdischarge was evoked. Hippocampal perfusion of sulpiride, a D2 receptor antagonist, enhanced dopamine release, which was more evident when an afterdischarge was induced in kindled rats. In addition, sulpiride perfusion was associated with longer seizure duration. Functional autoradiography experiments revealed increased [(35)S]GTP?S incorporation as a consequence of D2-like receptor activation in different brain areas of fully kindled animals, including the ventral hippocampus. The present study reveals that hippocampal kindling is associated with alterations in dopamine release and D2-like receptor-induced neurotransmission. PMID:23085386

Alcantara-Gonzalez, David; Floran, Benjamin; Escartin, Erik; Rocha, Luisa

2012-10-18

133

Depletion-induced demixing in aqueous protein-polysaccharide solutions.  

PubMed

We explore the separation of aqueous protein-polysaccharide solutions into two liquid phases. In particular, we have studied the combinations beta-lactoglobulin/pullulan, alpha-lactalbumin/pullulan, and other examples from the literature under a variety of conditions such as varying salt content, pH (in most cases at the isoelectric point), and protein radius. We restrict ourselves to relatively small proteins (globular) and long polysaccharide chains. The mechanism behind the phase separation is explained in terms of the depletion interaction (i.e., the cross-interaction) in a suspension of small spheres (proteins) immersed in a semidilute solution of coils (polysaccharide) forming an entangled network. Weak attractions between the spheres have been taken into account by assuming the formation of small clusters. As a general rule, we find that the depletion free energy per protein particle governing the protein partitioning in the phase equilibrium is linear in the polysaccharide concentration over the whole range of experimentally accessible coexistence curves. Furthermore, the proportionality constant is shown to be a very useful quantity to understand the characteristics of the coexistence curves. The linearity thus found is supported by theoretical arguments developed by de Gennes and Odijk. PMID:11777377

Wang, S; van Dijk, J A; Odijk, T; Smit, J A

2001-01-01

134

The Extent of Desmoglein 3 Depletion in Pemphigus Vulgaris Is Dependent on Ca2+-Induced Differentiation  

PubMed Central

Pemphigus vulgaris (PV) is an autoimmune disease of the skin and mucous membranes and is characterized by development of autoantibodies against the desmosomal cadherins desmoglein (Dsg) 3 and Dsg1 and formation of intraepidermal suprabasal blisters. Depletion of Dsg3 is a critical mechanism in PV pathogenesis. Because we did not detect reduced Dsg3 levels in keratinocytes cultured for longer periods under high-Ca2+ conditions, we hypothesized that Dsg depletion depends on Ca2+-mediated keratinocyte differentiation. Our data indicate that depletion of Dsg3 occurs specifically in deep epidermal layers both in skin of patients with PV and in an organotypic raft model of human epidermis incubated using IgG fractions from patients with PV. In addition, Dsg3 depletion and loss of Dsg3 staining were prominent in cultured primary keratinocytes and in HaCaT cells incubated in high-Ca2+ medium for 3 days, but were less pronounced in HaCaT cultures after 8 days. These effects were dependent on protein kinase C signaling because inhibition of protein kinase C blunted both Dsg3 depletion and loss of intercellular adhesion. Moreover, protein kinase C inhibition blocked suprabasal Dsg3 depletion in cultured human epidermis and blister formation in a neonatal mouse model. Considered together, our data indicate a contribution of Dsg depletion to PV pathogenesis dependent on Ca2+-induced differentiation. Furthermore, prominent depletion in basal epidermal layers may contribute to the suprabasal cleavage plane observed in PV.

Spindler, Volker; Endlich, Alexander; Hartlieb, Eva; Vielmuth, Franziska; Schmidt, Enno; Waschke, Jens

2011-01-01

135

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

136

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

PubMed Central

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

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

1988-01-01

137

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

138

Bromocriptine, a dopamine D 2 receptor agonist with the structure of the amino acid ergot alkaloids, induces neurite outgrowth in PC12 cells  

Microsoft Academic Search

To investigate whether dopamine agonists induce neurite outgrowth, we examined the effects of dopamine D2 receptor agonists such as bromocriptine, talipexole, and pramipexole in PC12 cells, a well-studied model of neurite outgrowth. Bromocriptine significantly induced neurite outgrowth in a concentration-dependent manner. Neither talipexole nor pramipexole induced neurite outgrowth. Domperidone and sulpiride, dopamine D2 receptor antagonists, did not have any effect

Toru Oda; Toshiaki Kume; Yasuhiko Izumi; Yuki Takada-Takatori; Tetsuhiro Niidome; Akinori Akaike

2008-01-01

139

Comparison of the time courses of selective gene expression and dopaminergic depletion induced by MPP+ in MN9D cells.  

PubMed

Parkinson's disease (PD) is a common neurodegenerative disease characterized by progressive loss of midbrain dopaminergic neurons with unknown etiology. MPP+ (1-methyl-4-phenylpyridinium ion) is the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces Parkinson's-like symptoms in humans and animals. MPTP/MPP+ produces selective dopaminergic neuronal degeneration, therefore, these agents are commonly used to study the pathogenesis of PD. However, the mechanisms of their toxicity have not been fully elucidated. Recently, we reported in a microarray study using a midbrain-derived dopaminergic neuronal cell line, MN9D, that MPP+ induced significant changes in a number of genes known to be associated with the dopaminergic system. In this study, we investigated the expression time courses of six genes using real-time RT-PCR, and compared them with the progressive dopaminergic depletion caused by MPP+. Our data showed that dopamine content was significantly decreased after 0.5h of MPP+ (200 microM) exposure and was completely depleted after 40 h. The expression of Gpr37, which is closely related to the pathogenesis of autosomal recessive juvenile Parkinsonism, was up-regulated after 0.5h, and stayed up-regulated up to 48 h. Txnip, which is critical to the adjustment of cellular redox status, was down-regulated after 1h and stayed down-regulated up to 48 h. Ldh1 and Cdo1, which are also involved in oxidative stress, were down-regulated after 16 h and stayed down-regulated up to 48 h. Two pro-apoptotic genes, Egln3 and Bnip3, were down-regulated after 2 and 4h, and stayed down-regulated up to 48 h. These findings suggested that the time course of expression for multiple genes correlated with the dopaminergic depletion; and MPP+-induced neurotoxicity in MN9D cells could be used as a model to further explore the roles of these and other genes in the pathogenesis and possible treatment of PD. PMID:18069091

Wang, Jianyong; Duhart, Helen M; Xu, Zengjun; Patterson, Tucker A; Newport, Glenn D; Ali, Syed F

2007-11-04

140

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

PubMed Central

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

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

2011-01-01

141

Reversal of the increase in apomorphine-induced stereotypy and aggression in REM sleep deprived rats by dopamine agonist pretreatments  

Microsoft Academic Search

REM sleep deprivation (REMSD) induces augmented responses to dopaminergic agonists. Prolonged administration of neuroleptics induces a similar state, probably by the production of supersensitivity of dopaminergic receptors. Such a supersensitive state could be induced by REMSD as a result of impairment of dopamine neurotransmission. In order to test this hypothesis, bromocriptine, nomifensine, amphetamine,l-dopa, imipramine and electroconvulsive shock (ECS) were administered

L. R. P. Troncone; T. M. S. Ferreira; S. Braz; N. G. Silveira Filho; S. Tufik

1988-01-01

142

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

PubMed

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

Nickla, Debora L; Totonelly, Kristen

2011-08-23

143

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

PubMed Central

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

Nickla, Debora L.; Totonelly, Kristen

2011-01-01

144

Hemin-induced necroptosis involves glutathione depletion in mouse astrocytes  

Microsoft Academic Search

Intracerebral hemorrhage (ICH) is a devastating neurological injury associated with significant mortality. Astrocytic inflammation may contribute to the pathogenesis of ICH, although the underlying cellular mechanisms remain unclear. In this study, the hemoglobin oxidation by-product, hemin, concentration-dependently induced necroptotic cell death in cortical astrocytes within 5 h of treatment. Hemin-induced cell death was preceded by increased inflammatory gene expression (COX-2, IL-1?,

Melissa D. Laird; Chandramohan Wakade; Cargill H. Alleyne; Krishnan M. Dhandapani

2008-01-01

145

Dopamine D1 and NMDA Receptors and ERK Mediate Neuronal Morphological Changes Induced by Repeated Cocaine Administration  

PubMed Central

The development of drug addiction involves persistent cellular and molecular changes in the central nervous system. The brain dopamine and glutamate systems play key roles in mediating drug-induced neuroadaptation. Changes in dendritic morphology in medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and caudate putamen (CPu) accompany drug-induced enduring behavioral and molecular changes. We have investigated the potential involvement of dopamine D1 and D2 receptors, the N-methyl-D-aspartate (NMDA) receptor, and the extracellular signal-regulated kinase (ERK) in dendritic morphological changes induced by repeated cocaine administration. We show that either a genetic mutation or pharmacological blockade of dopamine D1 receptors attenuated cocaine-induced changes in both dendritic branching and spine density of MSNs in the shell of the NAc and CPu. In contrast, antagonism of dopamine D2 receptors had no obvious effect on changes in dendritic branching but had a partial effect on changes in spine density of MSNs in these brain regions following repeated cocaine injections. Pharmacological inhibition of either NMDA receptors or ERK attenuated cocaine-induced changes in both dendritic branching and spine density of MSNs in the shell of the NAc and CPu. These results suggest that dopamine D1 and NMDA receptors and ERK contribute significantly to neuronal morphological changes induced by repeated exposure to cocaine.

Ren, Zhihua; Sun, Wei-Lun; Jiao, Hongyuan; Zhang, Dongsheng; Kong, Han; Wang, Xinkang; Xu, Ming

2010-01-01

146

Protective effect of 7-nitroindazole against DSP4 induced noradrenaline depletion in mouse hippocampus  

Microsoft Academic Search

Summary.   N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a selective noradrenaline (NA) uptake blocker, capable of inducing\\u000a a long-lasting depletion of NA in some noradrenergic axon terminals originating from the locus coeruleus in rodents. Pretreatment\\u000a with 7-nitroindazole, a fairly selective inhibitor of neuronal nitric oxide synthase in vivo, partially prevented DSP-4 induced\\u000a NA depletion in mouse hippocampus measured seven days after the neurotoxic insult.

É. Szökõ; D. Haberle; A. S. Halász; K. Tekes; K. Magyar

2001-01-01

147

Sepsis Induces Diaphragm Electron Transport Chain Dysfunction and Protein Depletion  

Microsoft Academic Search

Rationale: Sepsis significantly alters skeletal muscle mitochondrial function, but the mechanisms responsible for this abnormality are unknown. Objectives: We postulated that endotoxin elicits specific changes in electron transport chain proteins that produce derangements in mitochondrial function. To examine this issue, we compared the effects of endotoxin-induced sepsis on mitochondrial ATP (adeno- sine triphosphate) formation and electron transport chain protein composition.

Leigh A. Callahan; Gerald S. Supinski

2005-01-01

148

Running wheel exercise enhances recovery from nigrostriatal dopamine injury without inducing neuroprotection.  

PubMed

Forced use of the forelimb contralateral to a unilateral injection of the dopaminergic neurotoxin 6-hydroxydopamine can promote recovery of motor function in that limb and can significantly decrease damage to dopamine terminals. The present study was conducted to determine (1) whether a form of voluntary exercise, wheel running, would improve motor performance in rats with such lesions, and (2) whether any beneficial effects of wheel running are attributable to ameliorating the dopaminergic damage. In experiment 1, rats were allowed to run in exercise wheels or kept in home cages for 2 1/2 weeks, then given stereotaxic infusions of 6-hydroxydopamine into the left striatum. The rats were replaced into their original environments (wheels or home cages) for four additional weeks, and asymmetries in forelimb use were quantified at 3, 10, 17, and 24 days postoperatively. After killing, dopaminergic damage was assessed by both quantifying 3 beta-(4-iodophenyl)tropan-2 beta-carboxylic acid methyl ester ([(125)I]RTI-55) binding to striatal dopamine transporters and counting tyrosine hydroxylase-positive cells in the substantia nigra. Exercised 6-hydroxydopamine-infused rats showed improved motor outcomes relative to sedentary lesioned controls, effects that were most apparent at postoperative days 17 and 24. Despite this behavioral improvement, 6-hydroxydopamine-induced loss of striatal dopamine transporters and tyrosine hydroxylase-positive nigral cells in exercised and sedentary groups did not differ. Since prior studies suggested that forced limb use improves motor performance by sparing nigrostriatal dopaminergic neurons from 6-hydroxydopamine damage, experiment 2 used a combined regimen of forced plus voluntary wheel running. Again, we found that the motor performance of exercised rats improved more rapidly than that of sedentary controls, but that there were no differences between these groups in the damage produced by 6-hydroxydopamine. It appears that voluntary exercise can facilitate recovery from partial nigrostriatal injury, but it does so without evident sparing of dopamine nerve terminals. PMID:17157992

O'Dell, S J; Gross, N B; Fricks, A N; Casiano, B D; Nguyen, T B; Marshall, J F

2006-12-08

149

Mechanism of dopamine D2 receptor-induced Ca(2+) release in PC-12 cells.  

PubMed

Intracellular Ca(2+) levels are tightly regulated in the neuronal system. The loss of Ca(2+) homeostasis is associated with many neurological diseases and neuropsychiatric disorders such as Parkinson's, Alzheimer's, and schizophrenia. We investigated the mechanisms involved in intracellular Ca(2+) signaling in PC-12 cells. The stimulation of NGF-differentiated PC-12 cells with 3?M ATP caused an early Ca(2+) release followed by a delayed Ca(2+) release. The delayed Ca(2+) release was dependent on prior ATP priming and on dopamine secretion by PC-12 cells. Delayed Ca(2+) release was abolished in the presence of spiperone, suggesting that it is due to the activation of D2 dopamine receptors (D2R) by dopamine secreted by PC-12 cells. This was shown to be independent of PKA activation but dependent on PLC activity. An endocytosis step was required for inducing the delayed Ca(2+) release. Given the importance of calcyon in clathrin-mediated endocytosis, we verified the role of this protein in the delayed Ca(2+) release phenomenon. siRNA targeting of calcyon blocked the delayed Ca(2+) release, decreased ATP-evoked IP3R-mediated Ca(2+) release, and impaired subsequent Ca(2+) oscillations. Our results suggested that calcyon is involved in an unknown mechanism that causes a delayed IP3R-mediated Ca(2+) release in PC-12 cells. In schizophrenia, Ca(2+) dysregulation may depend on the upregulation of calcyon, which maintains elevated Ca(2+) levels as well as dopamine signaling. PMID:24055909

Frégeau, Marc-Olivier; Carrier, Maxime; Guillemette, Gaétan

2013-09-19

150

Cyclophosphamide-induced apoptosis in COV434 human granulosa cells involves oxidative stress and glutathione depletion.  

PubMed

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 depletion or treatment with 4-hydroperoxycyclophosphamide (4HC), a preactivated form of cyclophosphamide, induces apoptosis, (2) GSH depletion potentiates 4HC-induced apoptosis, and (3) 4HC-induced apoptosis is mediated by GSH depletion and oxidative stress. Cells were treated with buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, with or without follicle stimulating hormone (FSH) or serum. A significant increase in the number of apoptotic cells, assessed by terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate nick-end labeling (TUNEL) and Hoechst 33342 staining, occurred with BSO treatment. Treatment with 4HC dose-dependently induced apoptosis by TUNEL, Hoechst staining, and caspase 3 activation. Treatment with 4HC caused an increase in reactive oxygen species generation, measured by dichlorofluorescein fluorescence, oxidative DNA damage, measured by 8-hydroxyguanosine immunostaining, and an oxidation of the redox potential for the oxidized glutathione/reduced glutathione couple. Total intracellular GSH declined after 4HC treatment, preceding the onset of cell death. Treatment with antioxidants inhibited 4HC-induced apoptosis. Combined treatment with BSO and 4HC caused greater induction of apoptosis than either treatment alone. These findings are consistent with roles for oxidative stress and GSH depletion in mediating the induction of apoptosis in COV434 cells by cyclophosphamide. PMID:17434952

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

2007-04-13

151

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

2013-08-01

152

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

PubMed Central

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.

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

2013-01-01

153

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

PubMed

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

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

2013-07-16

154

Repeated amphetamine pretreatment alters the responsiveness of striatal dopamine-stimulated adenylate cyclase to amphetamine-induced desensitization.  

PubMed

The repeated daily administration of moderate doses of amphetamine results in an augmentation of the behavioral response to subsequent amphetamine challenge. One feature of the augmentation is a shift in the type of perseverative behaviors to those generally associated with higher acute doses of the drug. Consistent with these observations, rats pretreated with six daily injections of amphetamine (3 mg/kg) exhibited primarily oral stereotypies to a challenge dose of 2.5 mg/kg of amphetamine, whereas control animals exhibited focused sniffing and repetitive head movements. Previously we found that the acute administration of amphetamine or methylphenidate only at doses which induce oral stereotypies promotes a rapid desensitization of striatal dopamine-stimulated adenylate cyclase. We therefore examined the effects of repeated amphetamine pretreatment on this index of D1 dopamine receptors. The administration of 2.5 mg/kg of amphetamine produced a 2-fold shift to the right in the concentration-response curve for dopamine-stimulated adenylate cyclase in animals pretreated with amphetamine, but not in saline pretreated controls. No effect of the chronic amphetamine pretreatment on dopamine stimulated cyclase in the absence of amphetamine challenge was observed. The binding of [3H]cis-flupenthixol to striatal D1 dopamine receptors was not affected by acute or chronic amphetamine. These results suggest a relationship between stimulant-induced desensitization of striatal D1 dopamine receptors and the induction of oral stereotypies. PMID:2956412

Barnett, J V; Segal, D S; Kuczenski, R

1987-07-01

155

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

PubMed Central

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.

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

2012-01-01

156

Efficient Treg depletion induces T-cell infiltration and rejection of large tumors.  

PubMed

There are a number of factors that hamper immunotherapy of cancer. For example, tumors exhibit an aberrant vasculature that appears to form a barrier against T-cell infiltration. Another major obstacle is created by Treg. So far, conventional depletion of Treg with anti-CD25 antibodies, which eliminate only 70% of Treg, has failed to significantly reduce the growth of established tumors. Using Foxp3.LuciDTR-4 mice, we show here that 90-95% Treg depletion resulted in complete regression of large established tumors, whereas 70% depletion was ineffective. The extensive Treg depletion induced a number of processes that are critical for tumor rejection, including activation of tumor-specific CD8(+) T cells and enhanced infiltration of these cells into the tumor. The precise mechanism of enhanced infiltration is not known, but normalization of the tumor vasculature is assumed to assist infiltration. Indeed, we observed that 90% Treg depletion caused normalization of the tumor vasculature as indicated by a reduction in leakiness and the number of dilated vessels. These results suggest that for clinical immunotherapy of cancer, it would be desirable to have reagents that allow high-level depletion of Treg, which, in conjunction with treatment modalities such as vaccination, may concomitantly increase T-cell activation and infiltration. PMID:21072887

Li, Xingrui; Kostareli, Efterpi; Suffner, Janine; Garbi, Natalio; Hämmerling, Günter J

2010-12-01

157

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

158

Effect of GBR 12909 and fluoxetine on the acute and long term changes induced by MDMA (‘ecstasy’) on the 5HT and dopamine concentrations in mouse brain  

Microsoft Academic Search

We examined the long term effect of 3,4 methylenedioxymethamphetamine (MDMA, 10, 20 and 30 mg\\/kg, i.p.) on the cerebral 5-hydroxytryptamine (5-HT) and dopamine content in Swiss Webster mice. Three injections of MDMA (20 or 30 mg\\/kg, i.p.) given 3 h apart produced a marked depletion in the striatal content of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid

E. O'Shea; B. Esteban; J. Camarero; A. R. Green; M. I. Colado

2001-01-01

159

Pharmacological mechanisms mediating phencyclidine-induced apoptosis of striatopallidal neurons: the roles of glutamate, dopamine, acetylcholine and corticosteroids.  

PubMed

Phencyclidine (PCP) has recently been shown to induce apoptosis of a subpopulation of striatopallidal neurons which lie in the dorsomedial caudate-putamen. The pharmacological mechanisms underlying this PCP-induced striatal death were investigated in a series of small experiments. Striatal silver-methenamine-stained sections from rats injected acutely with dizocilpine (MK-801; 1.5-5 mg/kg, i.p.) were analysed to determine whether other non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists could induce apoptotic-like changes in striatal cells. The effects of amphetamine (3-12 mg/kg, i.p.) were similarly investigated as PCP can elevate extracellular dopamine levels and dopamine has the potential to be neurotoxic. The potential involvement of dopamine transmission in PCP-induced striatal apoptosis was also tested by determining the effect of co-administering SCH23390 (D1 dopamine receptor antagonist) and quinpirole (D2 dopamine receptor agonist) on PCP (80 mg/kg, s.c.)-induced striatal apoptotic-like cell death. Equivalent experiments were performed using scopolamine (cholinergic antagonist) as this drug blocks PCP-induced damage of the retrosplenial cortex and RU38486 (corticosteroid receptor antagonist) as a similar subpopulation of striatal neurons undergoes apoptosis following dexamethasone administration. Injection of neither MK-801 nor amphetamine induced elevations of apoptotic-like cells in the striatum nor did co-administration of SCH23390 or scopolamine affect the levels of PCP-induced striatal cell death. In contrast, quinpirole elevated the levels of PCP-induced apoptotic-like striatal cell death and RU38486 markedly reduced it. Within the retrosplenial cortex, scopolamine lowered PCP-induced apoptotic-like cell death whereas RU38486 was without effect. These results suggest that PCP-induced striatal apoptosis results from a corticosteroid-dependent mechanism. The results further demonstrate that different pathological mechanisms underlie PCP-induced neuronal damage in the striatum and the retrosplenial cortex. PMID:10650124

Griffiths, M R; Cooper, A J; Barber, D J; Mitchell, I J

2000-02-01

160

Renal papillary cytoplasmic granularity and potassium depletion induced by carbonic anhydrase inhibitors in rats.  

PubMed

Renal papillary cytoplasmic granularity (RPCG) induced by carbonic anhydrase inhibitors (CAIs) in rats is characterized by the accumulation of dense secondary lysosomes in epithelial, endothelial, and interstitial cells and may be related to drug-induced potassium depletion. Female Sprague-Dawley rats were given the CAI, acetazolamide, by gavage. Half were supplemented with 1% potassium chloride in the drinking water. Two treated groups were allowed to recover for 1 or 2 mo. Potassium supplementation inhibited RPCG by 80% but produced little amelioration of the mild 13% decrease in serum potassium induced by 200 mg/kg/day acetazolamide for 28 days. Acetazolamide-induced RPCG is reversible because 1- and 2-mo recovery periods decreased the incidence by 75% and 80%, respectively. The results support the hypothesis that RPCG is related to potassium depletion secondary to carbonic anhydrase inhibition. Because supplementation of potassium chloride had little effect on serum potassium, these data suggest that depletion of renal medullary potassium content is important in the pathogenesis of RPCG as previously suggested by others. Other types of diuretics that produce hypokalemia as a side effect may not deplete medullary potassium since RPCG has not been reported in humans or animals given these drugs. PMID:8115822

Owen, R A; Durand-Cavagna, G; Molon-Noblot, S; Boussiquet-Leroux, C; Berry, P H; Tonkonoh, N; Peter, C P; Gordon, L R

161

Hemifusion of Giant Lipid Vesicles Induced by a Small Transient Osmotic Depletion Force  

Microsoft Academic Search

Abstract We observed hemifusion of giant unilamellar vesicles (GUVs) by injecting a small volume,of 5% polyethylene glycol solution in the vicinity for a short time. The induced transient osmotic depletion attraction between two bilayers was smaller than the corresponding van der Waals force, yet hemifusion readily occurred for some lipid compositions. This might imply that the energy barrier for hemifusion

Chang-chun Lee; Shuo Qian; Yen Sun; Huey W. Huang

162

EFFECTS OF SYSTEMIC NEUTROPHIL DEPLETION ON LPS-INDUCED AIRWAY DISEASE  

EPA Science Inventory

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

163

Amphetamine, scopolamine- and caffeine-induced locomotor activity following 6-hydroxydopamine lesions of the mesolimbic dopamine system  

Microsoft Academic Search

As previously reported, 6-hydroxydopamine (6-OHDA) lesions to the region of the nucleus accumbens blocked the locomotor activation induced by low doses of d-amphetamine, and produced a supersensitive locomotor response to the dopamine (DA) agonist, apomorphine. This same lesion, however, failed to block the locomotor activation induced by scopolamine or caffeine. These results suggest that scopolamine and caffeine activate locomotion in

Eileen M. Joyce; George F. Koob

1981-01-01

164

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

PubMed

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

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

2012-07-27

165

Confinement-Induced Solidification of Colloid-Polymer Depletion Mixtures  

NASA Astrophysics Data System (ADS)

Using a model colloid-polymer suspension, we show that confinement induces solidification in attractive colloidal suspensions via a fundamentally different route from that active in hard sphere colloidal suspensions. For a range of polymer concentrations, the suspensions undergo a phase transition from a colloidal fluid of clusters to a colloidal gel as confinement increases while polymer and particle concentration are held constant. In both fluid- and solidlike attractive suspensions, effects of confinement on the structure and dynamics appear at much larger thicknesses than for hard-sphere suspensions. The solidification does not originate from structuring of the colloids by the walls. Instead, by analyzing cluster size distributions in the fluid phase and particle dynamics in the gel phase as a function of confinement, we find that the strength of the effective interparticle attraction increases as the samples are confined. We show that the increase in the effective attraction can be understood as a consequence of the increasing importance of excluded volume due to the walls to the free energy of the polymer as confinement is increased.

Spannuth, Melissa; Conrad, Jacinta C.

2012-07-01

166

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

Microsoft Academic Search

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

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

2006-01-01

167

Rotenone increases glutamate-induced dopamine release but does not affect hydroxyl-free radical formation in rat striatum.  

PubMed

Impairment of the mitochondrial complex I has been found in Parkinson's disease and recently long-term treatment with the complex I inhibitor rotenone led to neurodegeneration and Lewy body-like inclusions in rats. To investigate the relationship of free radical formation, complex I inhibition, and dopamine release, rotenone (15 mg/kg s.c.) was injected in male Sprague Dawley rats. Complex I inhibition was measured in the striatum and substantia nigra using the lactate accumulation assay. Dopamine release and free radical formation was determined using striatal microdialysis in combination with the salicylate hydroxylation assay. In a second experiment, glutamate (10 mM) stimulation via the microdialysis probe was used to provoke hydroxyl radical formation and dopamine release 60 min after rotenone or vehicle pretreatment. Rotenone significantly increased striatal and nigral lactate levels. However, rotenone did not produce a significant increase in hydroxyl radical formation and dopamine release, but led to a pronounced hypokinesia. In contrast, rotenone in comparison to vehicle pretreatment produced a significant augmentation of glutamate-induced dopamine release (67-fold and 31-fold increase, respectively) and did not affect the glutamate-induced hydroxyl free radical formation (23-fold and 21-fold increase, respectively). The present study demonstrates that a single systemic rotenone administration does not lead to neurotoxicity, but rather to enhanced glutamate-induced dopamine release with no further increase of hydroxyl free radical formation. Thus, acute complex I inhibition in the presence or absence of high extracellular dopamine and glutamate levels is not critically involved in the formation of hydroxyl free radicals. PMID:14515342

Leng, Andreas; Feldon, Joram; Ferger, Boris

2003-12-01

168

Hydrogen peroxide induces loss of dopamine transporter activity: a calcium-dependent oxidative mechanism.  

PubMed

H2O2 dose dependently inhibited dopamine uptake in PC12 cells and in striatal synaptosomes. Treatment with H2O2 resulted in a reversible reduction in Vmax, with no effect on its Km value. This suppressive effect of H2O2 could be relieved by reducing agents (dithiothreitol and cysteine). Furthermore, an oxidizer (dithiodipyridine) also markedly suppressed the dopamine transporter (DAT). Oxidative stress therefore might contribute to the action of H2O2. H2O2 appeared to modify DAT at both extracellular and intracellular sites because cumene-H2O2 (a radical generator mostly restricted to plasma membranes) at high concentrations also slightly suppressed DAT activity and the intracellular overexpression of catalase ameliorated the inhibitory effect of H2O2. Internalization was unlikely to be involved because concanavalin A, which blocked endocytosis, did not prevent the H2O2-evoked inhibition of DAT activity. Interestingly, H2O2 treatment evoked a Ca2+ influx in PC12 cells. Moreover, removal of external calcium by EGTA or reduction in the intracellular calcium level using BAPTA-AM reversed the inhibitory effect of H2O2. Conversely, depletion of intracellular calcium stores using thapsigargin did not affect the reduction in DAT activity by H2O2. Collectively, our results indicate that the DAT, one of the most important proteins controlling the dopaminergic system, is also a redox sensor. In addition, H2O2 might suppress the DAT by a Ca2+-dependent oxidative pathway. PMID:12911632

Huang, Chuen-Lin; Huang, Nai-Kuei; Shyue, Song-Kun; Chern, Yijuang

2003-09-01

169

ATP depletion does not account for apoptosis induced by inhibition of mitochondrial electron transport chain in human dopaminergic cells  

Microsoft Academic Search

As the mitochondrial electron transport chain (ETC) is necessary for life, its inhibition results in cell death. To date, ETC complex (I–IV) inhibitors (ETCIs) have been thought to induce ATP depletion, triggering cellular apoptosis. To clarify whether the depletion of intracellular ATP is relevant to apoptosis induced by ETCIs, we conducted comparative studies using oxidative phosphorylation inhibitors (OPIs), including a specific

Masahiko Watabe; Toshio Nakaki

2007-01-01

170

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

171

Preventive effect of zelandopam, a dopamine D1 receptor agonist, on cisplatin-induced acute renal failure in rats  

Microsoft Academic Search

To elucidate the role of peripheral dopamine D1 receptors in cisplatin-induced acute renal injury, effect of zelandopam (YM435, (?)-(S)-4-(3,4-dihydroxyphenyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride hydrate), a selective renal dopamine D1 receptor agonist, on cisplatin-induced acute renal failure in rats was studied. Rats were divided into six groups: control, cisplatin and cisplatin plus zelandopam (30, 100, 300 mg\\/kg p.o. twice, 75 and 15 min before

Takeyuki Yatsu; Motonori Aoki; Osamu Inagaki

2003-01-01

172

Effects of CD8 depletion on retinal soluble antigen induced experimental autoimmune uveoretinitis.  

PubMed Central

During the later stages of soluble-antigen (sAg)-induced experimental autoimmune uveoretinitis (EAU), an increase in the relative number of CD8+ lymphocytes has been observed at the site of inflammation in the retina. It has been suggested that these late-appearing CD8+ cells might down-regulate this acute disease process. To determine the role of the CD8+ cells in EAU, Lewis rats were depleted of CD8+ cells prior to and during disease and the enucleated eyes examined histologically. The spleen cells from CD8-depleted rats were also examined for their ability to respond to concanavalin A (Con A) and to allogeneic targets as determined by mixed lymphocyte reaction (MLR) and cytotoxicity assays. The results suggest that depleting CD8+ cells had no effect on the course of disease and that CD8+ cells do not play a crucial role in the immunoregulation of EAU. Images Figure 4 Figure 5

Calder, V L; Zhao, Z S; Wang, Y; Barton, K; Lightman, S L

1993-01-01

173

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

2013-05-31

174

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

PubMed Central

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

Errington, Timothy M.; Macara, Ian G.

2013-01-01

175

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

PubMed

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

Errington, Timothy M; Macara, Ian G

2013-09-23

176

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

177

Modulation of ventral tegmental area dopamine receptors inhibit nicotine-induced anxiogenic-like behavior in the central amygdala.  

PubMed

Nicotine, the major addictive substance in tobacco, increases the activity of the central amygdala (CeA). Amygdala is directly implicated in anxiety modulation and sends projections to the vicinity of the midbrain dopamine neurons, including the ventral tegmental area (VTA) which is a key area that controls nicotine dependence processes. In this study, the role of dopamine D(1) and D(2)/(3) receptors of the VTA on anxiogenic-like behavior induced with intra-CeA injection of nicotine has been investigated. Male Wistar rats with cannula aimed to the left CeA and the left VTA were submitted to the elevated plus-maze (EPM). The nicotine injection (1 ?g/rat) into the CeA decreased the percentage of open arm time and open arm entries, but not locomotor activity, indicating an anxiogenic-like response. Intra-VTA injection of a dopamine D1 receptor antagonist, SCH23390 (0.25 ?g/rat), and a dopamine D2/3 receptor antagonist, sulpiride (0.7 ?g/rat), inhibited the anxiogenic-like response caused by intra-CeA injection of nicotine. These results suggest that the relationship between the VTA and the CeA may be involved in nicotine-induced anxiogenic-like behavior via dopamine D(1) and D(2)/(3) receptors. An understanding of these cellular processes will be crucial for the development of new intervention to combat nicotine effect. PMID:23178824

Zarrindast, Mohammad Reza; Eslahi, Nafiseh; Rezayof, Ameneh; Rostami, Parvin; Zahmatkesh, Maryam

2012-11-21

178

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

PubMed

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

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

2007-04-27

179

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

SciTech Connect

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

Di Paolo, T.; Falardeau, P.

1987-08-31

180

Effects of chondroitin sulfate-C on bradykinin-induced proteoglycan depletion in rats.  

PubMed

Depletion of the proteoglycan content of articular cartilage was induced by injecting bradykinin (30-300 mumol/l, 50 microliters/knee) into the left knee articular cavities of rats 3 times a day for 2 days. The degree of the reduction in the intensity of histopathological safranin O staining was used as an index of proteoglycan depletion. Bradykinin reduced the cartilage proteoglycan contents of the knee joints of non-injected limbs in a dose-dependent manner and at 300 mumol/l markedly reduced these contents, but evoked no inflammatory changes. The extent of the reduction of the cartilage proteoglycan contents induced by bradykinin injection depended on the dose and injection frequency. Chondroitin sulfate-C (CAS 25322-46-7, Chondroitin ZS Tab) (30-1,000 mg/kg/day) administered orally to rats for 14 days inhibited the bradykinin-induced proteoglycan depletion of the articular cartilage in a dose-dependent manner. These results suggest that a reduction of the proteoglycan content of cartilage, like that associated with osteoarthritis, was induced by injecting bradykinin into the knee articular cavities of rats and chondroitin sulfate-C protected against this effect. PMID:10442204

Omata, T; Segawa, Y; Itokazu, Y; Inoue, N; Tanaka, Y

1999-07-01

181

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

PubMed Central

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

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

2013-01-01

182

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

Microsoft Academic Search

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

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

2000-01-01

183

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

PubMed Central

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

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

2008-01-01

184

The role of NAD+ depletion in the mechanism of sulfur mustard-induced metabolic injury.  

PubMed

Results of our previous studies on the chemical warfare agent sulfur mustard (2,2'-dichlorodiethyl sulfide) suggested that mustard-induced inhibition of glycolysis is not solely a function of NAD+ depletion. To define the role of NAD+ in mustard-induced metabolic injury, we examined the effects of mustard+/-niacinamide on energy metabolism in cultured human keratinocytes. Sulfur mustard caused concentration-dependent decreases in viable cell number and ATP content at 24 hours, but not earlier, and time- and concentration-dependent glycolytic inhibition and NAD+ depletion as early as 4 hours. Niacinamide partially protected NAD+ levels at all time points, but did not prevent adverse effects on glycolysis, intracellular ATP, or viable cell number. These results support our earlier conclusions and suggest that sulfur mustard may inhibit glycolysis directly. PMID:18330833

Martens, Margaret E; Smith, William J

2008-01-01

185

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

186

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

Microsoft Academic Search

Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections.

Argel Aguilar-Valles; Cecilia Flores; Giamal N. Luheshi; Lisa F. P. Ng

2010-01-01

187

Time course of prepulse inhibition disruption induced by dopamine agonists and NMDA antagonists: Effects of drug administration regimen  

Microsoft Academic Search

Prepulse inhibition (PPI) of acoustic startle response is impaired in patients with schizophrenia and in animals acutely treated with dopamine agonists and NMDA antagonists. In this study, we investigated the time course of PPI disruption induced by repeated amphetamine, quinpirole, phencyclidine (PCP), and dizocilpine (MK-801) treatment. We focused on how PPI disruption development was influenced by drug administration regimens, comparing

Ming Li; Wei He; Jing Chen

2011-01-01

188

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

EPA Science Inventory

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

189

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

190

Lead intoxication induces noradrenaline depletion, motor nonmotor disabilities, and changes in the firing pattern of subthalamic nucleus neurons.  

PubMed

Lead intoxication has been suggested as a high risk factor for the development of Parkinson disease. However, its impact on motor and nonmotor functions and the mechanism by which it can be involved in the disease are still unclear. In the present study, we studied the effects of lead intoxication on the following: (1) locomotor activity using an open field actimeter and motor coordination using the rotarod test, (2) anxiety behavior using the elevated plus maze, (3) "depression-like" behavior using sucrose preference test, and (4) subthalamic nucleus (STN) neuronal activity using extracellular single unit recordings. Male Sprague-Dawley rats were treated once a day with lead acetate or sodium acetate (20 mg/kg/d i.p.) during 3 weeks. The tissue content of monoamines was used to determine alteration of these systems at the end of experiments. Results show that lead significantly reduced exploratory activity, locomotor activity and the time spent on the rotarod bar. Furthermore, lead induced anxiety but not "depressive-like" behavior. The electrophysiological results show that lead altered the discharge pattern of STN neurons with an increase in the number of bursting and irregular cells without affecting the firing rate. Moreover, lead intoxication resulted in a decrease of tissue noradrenaline content without any change in the levels of dopamine and serotonin. Together, these results show for the first time that lead intoxication resulted in motor and nonmotor behavioral changes paralleled by noradrenaline depletion and changes in the firing activity of STN neurons, providing evidence consistent with the induction of atypical parkinsonian-like deficits. PMID:22421103

Sabbar, M; Delaville, C; De Deurwaerdère, P; Benazzouz, A; Lakhdar-Ghazal, N

2012-02-21

191

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

192

Purinergic mechanisms of lateral parabrachial nucleus facilitate sodium depletion-induced NaCl intake  

Microsoft Academic Search

Purinergic receptors are present in the lateral parabrachial nucleus (LPBN), a pontine structure involved in the control of sodium intake. In the present study, we investigated the effects of ?,?-methyleneadenosine 5?-triphosphate (?,?-methylene ATP, selective P2X purinergic agonist) alone or combined with pyridoxalphosphate-6-azophenyl-2?,4?-disulfonic acid (PPADS, P2X purinergic antagonist) or suramin (non-selective P2 purinergic antagonist) injected into the LPBN on sodium depletion-induced

Miguel F. Menezes; Silas P. Barbosa; Carina A. F. De Andrade; José V. Menani; Patrícia M. De Paula

2011-01-01

193

Depletion of insulin receptor substrate 2 reverses oncogenic transformation induced by v-src  

Microsoft Academic Search

Aim:To investigate the role of insulin receptor substrate 2 (IRS-2) in oncogenic transformation induced by v-src.Methods:IRS-2 gene was silenced using small interfering RNAs (siRNAs). Nuclear translocation and interaction of IRS-2 with v-src was determined using subcellular fractionation, confocal microscopy, and immunoprecipitation. The activity of the cyclin D1 promoter and r-DNA promoter was measured with a luciferase assay.Results:Depletion of IRS-2 inhibited

Hong-zhi Sun; Lin Xu; Bo Zhou; Wei-jin Zang; Shu-fang Wu

2011-01-01

194

Increase in phosphoribosyl pyrophosphate induced by ATP and P, depletion in  

Microsoft Academic Search

A series of compounds that induce depletion of ATP and P1 when added to isolated rat hepatocytes were found to cause a remarkable, although transient, eleva- tion in the concentration of phosphoribosyl pyrophos- phate (PRPP) in these cells. After the addition of 5 mM fructose, xylitol, tagatose, or D-xylulose, PRPP increased from a basal value of 6 ± I nmol\\/g

FRANCOISE VINCENT; GEORGES VAN DEN BERGHE; HENRY-GERY HERS

195

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

PubMed

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

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

2010-06-26

196

Dopamine-dependent compensation maintains motor behavior in mice with developmental ablation of dopaminergic neurons.  

PubMed

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. PMID:24155314

Golden, Judith P; Demaro, Joseph A; Knoten, Amanda; Hoshi, Masato; Pehek, Elizabeth; Johnson, Eugene M; Gereau, Robert W; Jain, Sanjay

2013-10-23

197

Reactive oxygen species mediate dopamine-induced signaling in renal proximal tubule cells.  

PubMed

Intrarenally-produced dopamine (DA) induces a large increase in urinary sodium excretion mainly due to the inhibition of tubular sodium reabsorption. We aimed to study the participation of reactive oxygen species (ROS) in DA signaling pathway in proximal tubule cells. Our results show that DA increased ROS production in OK cells and indicate the mitochondria as the main source of ROS. DA also increased ERK1/2, superoxide dismutase (SOD) and transcription factor ?B (NF-?B) activity. These findings suggest that DA generates mitochondria-derived ROS that activate ERK1/2 and subsequently NF-?B and SOD activity at concentrations that exert a physiological regulation of renal function. PMID:23994527

Acquier, Andrea B; Mori Sequeiros García, Mercedes; Gorostizaga, Alejandra B; Paz, Cristina; Mendez, Carlos F

2013-08-28

198

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

2011-09-20

199

MDMA-evoked changes in the binding of dopamine D(2) receptor ligands in striatum of rats with unilateral serotonin depletion.  

PubMed

We earlier reported an anomalous 50% decrease in [(11)C]N-methylspiperone ([(11)C]NMSP) binding to dopamine D(2)-like receptors in living pig striatum after challenge with 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), suggesting either (1) a species peculiarity in the vulnerability of butyrophenone binding to competition from dopamine or (2) a novel consequence of synergistic actions of serotonin and dopamine at dopamine receptors. To distinguish these possibilities, we used microPET to test the vulnerability of [(11)C]NMSP binding in striatum of rats with unilateral telencephalic serotonin lesions, later verified by [(125)I]RTI-55 autoradiography. Baseline [(11)C]NMSP microPET recordings were followed by either saline or MDMA-HCl (4 mg/kg) injections (i.v.), and a second [(11)C]NMSP recording, culminating with injection of [(3)H]raclopride for autoradiography ex vivo. Neither MDMA-challenge nor serotonin lesion had any detectable effect on [(11)C]NMSP binding. In contrast, MDMA challenge increased receptor occupancy by [(3)H]raclopride ex vivo (relative to the B(max) in vitro) from 8% to 12%, and doubled the free ligand concentration in cerebral cortex, apparently by blocking hepatic CYP2D6. Assuming a single binding-site model, the increased [(3)H]raclopride binding indicated doubling of the apparent equilibrium dissociation constant in vivo (K(app) (d)), revealing a 2-fold increase in competition from endogenous dopamine at [(3)H]raclopride binding sites. The results favor hypothesis (1) that the remarkable vulnerability of [(11)C]NMSP binding in pig striatum to MDMA challenge does not generalize to the rodent. PMID:19768811

Ostergaard, Søren Dinesen; Alstrup, Aage Kristian Olsen; Gramsbergen, Jan Bert; Minuzzi, Luciano; Pedersen, Kasper; Jensen, Svend Borup; Doudet, Doris; Cumming, Paul

2010-01-01

200

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

201

Phencyclidine-induced locomotor hyperactivity is enhanced in mice after stereotaxic brain serotonin depletion.  

PubMed

The aim of this study was to investigate the role of forebrain serotonin projections in behavioural models with relevance to schizophrenia. Mice received stereotaxic micro-injections of the serotonin neurotoxin 5,7-dihydroxytryptamine into the median raphe nucleus (MRN). Two weeks later, MRN-lesioned mice were hyperactive at baseline and showed enhanced locomotor hyperactivity induced by phencyclidine. In contrast, no lesion effect was observed on the locomotor hyperactivity induced by amphetamine treatment or on prepulse inhibition. Lesioned mice showed a 68% depletion of serotonin in the hippocampus and 31% depletion in the striatum. These data confirm previous studies in rats that selective serotonin depletion in the brain enhances the effect of phencyclidine, but not amphetamine, on locomotor activity. This enhanced action of phencyclidine is likely to be mediated by the absence of serotonin-mediated behavioural inhibition in the hippocampus, leaving the psychostimulant effects of phencyclidine unopposed. Taken together with previous studies in rats, these studies in mice suggest that serotonin release in the dorsal hippocampus constitutes a behavioural inhibitory pathway normally involved in dampening excessive behavioural stimulation. Dysfunction of this pathway could be involved in psychosis and its stimulation could be a potential mechanism of action of antipsychotic drugs. PMID:18482774

Martin, Sally; van den Buuse, Maarten

2008-04-11

202

Depletion of Bmi-1 enhances 5-fluorouracil-induced apoptosis and autophagy in hepatocellular carcinoma cells  

PubMed Central

5-fluorouracil (5-FU) is one of the standard chemoradiotherapy regimens for hepatocellular carcinoma (HCC) treatment. B-cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) has been demonstrated to regulate proliferation. Additionally, Bmi-1 overexpression has been identified in HCC cell lines and correlates with the advanced invasive stage of tumor progression and poor prognosis. In this study, we examined the effects of 5-FU treatment on cell growth in HCC cells with or without Bmi-1 depletion. The IC50 values of 5-FU were significantly decreased to a greater extent in cells with Bmi-1 knockdown. Depletion of Bmi-1 increased sensitivity of the cells to 5-FU and increased apoptosis. Knockdown of endogenous Bmi-1 led to a substantial reduction in the levels of phospho-AKT and Bcl-2 with a concomitant increase in the levels of Bax. Additionally, 5-FU induced the conversion/turnover of microtubule-associated protein 1 light chain 3 (LC3). Knockdown of endogenous Bmi-1 led to an increase in the levels of Beclin-1 and the accumulation of LC3-II. Together, these findings reveal that Bmi-1 depletion enhanced the chemosensitivity of HCC cells by inducing apoptosis and autophagy, which is associated with the PI3K/AKT and Bcl-2/Beclin-1 pathways.

WU, JING; HU, DONG; ZHANG, RONGBO

2012-01-01

203

Resveratrol protects rat striatal slices against anoxia-induced dopamine release.  

PubMed

Incubation of rat striatal slices in anoxic medium caused significant alterations in dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) outputs; while DA release increased several times, 50% decline in DOPAC output was observed under this condition. Tissue ATP level, on the other hand, was decreased 40% by anoxia. Presence of resveratrol in the medium decreased anoxia-induced DA release in a concentration-dependent manner. Enhanced DA output, however, was declined slightly by epicatechine and catechine, and not altered significantly by morin hydrate and quercetin dehydrate which are other penolic compounds present in the red wine. In contrary to DA output, anoxia-induced decline in tissue ATP level was not ameliorated by resveratrol. In addition to anoxia, resveratrol, as observed with DA uptake blocker nomifensine, also reduced DA release stimulated by ouabain. Efficiencies of both resveratrol and nomifensine to attenuate ouabain-induced DA output, however, were closely dependent on ouabain concentration in the medium. These results indicate that some phenolic compounds, particularly resveratrol decrease anoxia-induced DA output and appear promising agents to improve the alterations occurred under anoxic-ischemic conditions. PMID:18438711

Gürsoy, Murat; Büyükuysal, R Levent

2008-04-26

204

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

205

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

206

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

NASA Astrophysics Data System (ADS)

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

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

1991-12-01

207

Caffeine produces contralateral rotation in rats with unilateral dopamine denervation: comparisons with apomorphine-induced responses  

Microsoft Academic Search

Like the dopamine agonist apomorphine, the methylxanthines caffeine, theophylline and theobromine produced dose-dependent contralateral rotation in rats with unilateral 6-hydroxydopamine denervation, a response considered to be dependent upon dopamine receptors rendered supersensitive. This response was also observed after the injection of the substances into the denervated striatum. Indeed, intrastriatal administration of caffeine into the dopamine denervated striatum produced, dose-dependently (1.0–50.0

M. Herrera-Marschitz; M. Casas; U. Ungerstedt

1988-01-01

208

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

209

Ceramide-induced formation of ROS and ATP depletion trigger necrosis in lymphoid cells.  

PubMed

In lymphocytes, Fas activation leads to both apoptosis and necrosis, whereby the latter form of cell death is linked to delayed production of endogenous ceramide and is mimicked by exogenous administration of long- and short-chain ceramides. Here molecular events associated with noncanonical necrotic cell death downstream of ceramide were investigated in A20 B lymphoma and Jurkat T cells. Cell-permeable, C6-ceramide (C6), but not dihydro-C6-ceramide (DH-C6), induced necrosis in a time- and dose-dependent fashion. Rapid formation of reactive oxygen species (ROS) within 30 min of C6 addition detected by a dihydrorhodamine fluorescence assay, as well as by electron spin resonance, was accompanied by loss of mitochondrial membrane potential. The presence of N-acetylcysteine or ROS scavengers like Tiron, but not Trolox, attenuated ceramide-induced necrosis. Alternatively, adenovirus-mediated expression of catalase in A20 cells also attenuated cell necrosis but not apoptosis. Necrotic cell death observed following C6 exposure was associated with a pronounced decrease in ATP levels and Tiron significantly delayed ATP depletion in both A20 and Jurkat cells. Thus, apoptotic and necrotic death induced by ceramide in lymphocytes occurs via distinct mechanisms. Furthermore, ceramide-induced necrotic cell death is linked here to loss of mitochondrial membrane potential, production of ROS, and intracellular ATP depletion. PMID:18191646

Villena, Joan; Henriquez, Mauricio; Torres, Vicente; Moraga, Francisco; Díaz-Elizondo, Jessica; Arredondo, Cristian; Chiong, Mario; Olea-Azar, Claudio; Stutzin, Andres; Lavandero, Sergio; Quest, Andrew F G

2007-12-23

210

Purinergic mechanisms of lateral parabrachial nucleus facilitate sodium depletion-induced NaCl intake.  

PubMed

Purinergic receptors are present in the lateral parabrachial nucleus (LPBN), a pontine structure involved in the control of sodium intake. In the present study, we investigated the effects of ?,?-methyleneadenosine 5'-triphosphate (?,?-methylene ATP, selective P2X purinergic agonist) alone or combined with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, P2X purinergic antagonist) or suramin (non-selective P2 purinergic antagonist) injected into the LPBN on sodium depletion-induced 1.8% NaCl intake. Male Holtzman rats with stainless steel cannulas implanted into the LPBN were used. Sodium depletion was induced by treating rats with the diuretic furosemide (20mg/kg of body weight) followed by 24h of sodium-deficient diet. Bilateral injections of ?,?-methylene ATP (2.0 and 4.0nmol/0.2?l) into the LPBN increased sodium depletion-induced 1.8% NaCl intake (25.3±0.8 and 26.5±0.9ml/120min, respectively, vs. saline: 15.2±1.3ml/120min). PPADS (4nmol/0.2?l) alone into the LPBN did not change 1.8% NaCl intake, however, pretreatment with PPADS into the LPBN abolished the effects of ?,?-methylene ATP on 1.8% NaCl intake (16.9±0.9ml/120min). Suramin (2.0nmol/0.2?l) alone into the LPBN reduced sodium depletion-induced 1.8% NaCl intake (5.7±1.9ml/120min, vs. saline: 15.5±1.1ml/120min), without changing 2% sucrose intake or 24h water deprivation-induced water intake. The combination of suramin and ?,?-methylene ATP into the LPBN produced no change of 1.8% NaCl intake (15.2±1.2ml/120min). The results suggest that purinergic P2 receptor activation in the LPBN facilitates NaCl intake, probably by restraining LPBN mechanisms that inhibit sodium intake. PMID:21129366

Menezes, Miguel F; Barbosa, Silas P; De Andrade, Carina A F; Menani, José V; De Paula, Patrícia M

2010-12-01

211

Mitochondrial DNA depletion induces radioresistance by suppressing G2 checkpoint activation in human pancreatic cancer cells.  

PubMed

We hypothesized that mitochondrial function regulates cell cycle checkpoint activation and radiosensitivity. Human pancreatic tumor cells (MiaPaCa-2, rho(+)) were depleted of mitochondrial DNA (rho degrees ) by culturing cells in the presence of ethidium bromide. Depletion of mitochondrial DNA was verified by PCR amplification of total DNA using primer pairs specific for mitochondrial DNA. Loss of mitochondrial DNA decreased plating efficiency and the percentage of cells in S phase. Exponential cultures were irradiated with 2, 4 and 6 Gy (dose rate: 0.83 Gy/min) of ionizing radiation and harvested for determination of cell viability, growth and cell cycle phase distributions. Rho degrees cells were radioresistant compared to rho(+) cells, with a dose-modifying factor (DMF) of 1.6. Although cell growth was significantly inhibited in irradiated rho(+) cells compared to unirradiated control cells, the inhibition in Rho degrees cells was minimal. In addition, mitochondrial DNA depletion suppressed radiation-induced G(2) checkpoint activation, which was accompanied by increases in both cyclin B1 and CDK1. These results suggest that mitochondrial function may regulate cell cycle checkpoint activation and radiosensitivity in pancreatic cancer cells. PMID:19580493

Cloos, Carla R; Daniels, David H; Kalen, Amanda; Matthews, Katee; Du, Juan; Goswami, Prabhat C; Cullen, Joseph J

2009-05-01

212

Mitochondrial DNA Depletion Induces Radioresistance by Suppressing G2 Checkpoint Activation in Human Pancreatic Cancer Cells  

PubMed Central

We hypothesized that mitochondrial function regulates cell cycle checkpoint activation and radiosensitivity. Human pancreatic tumor cells (MiaPaCa-2, rho+) were depleted of mitochondrial DNA (rho°) by culturing cells in the presence of ethidium bromide. Depletion of mitochondrial DNA was verified by PCR amplification of total DNA using primer pairs specific for mitochondrial DNA. Loss of mitochondrial DNA decreased plating efficiency and the percentage of cells in S phase. Exponential cultures were irradiated with 2, 4 and 6 Gy (dose rate: 0.83 Gy/min) of ionizing radiation and harvested for determination of cell viability, growth and cell cycle phase distributions. Rho° cells were radioresistant compared to rho+ cells, with a dose-modifying factor (DMF) of 1.6. Although cell growth was significantly inhibited in irradiated rho+ cells compared to unirradiated control cells, the inhibition in Rho° cells was minimal. In addition, mitochondrial DNA depletion suppressed radiation-induced G2 checkpoint activation, which was accompanied by increases in both cyclin B1 and CDK1. These results suggest that mitochondrial function may regulate cell cycle checkpoint activation and radio-sensitivity in pancreatic cancer cells.

Cloos, Carla R.; Daniels, David H.; Kalen, Amanda; Matthews, Katee; Du, Juan; Goswami, Prabhat C.; Cullen, Joseph J.

2009-01-01

213

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

SciTech Connect

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

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

1988-03-01

214

Deferoxamine blocks death induced by glutathione depletion in PC 12 cells.  

PubMed

The purpose of the present work was to investigate the mechanisms by which glutathione depletion induced by treatment with buthionine sulfoximine (BSO) led within 24-30 h to PC 12 cells apoptosis. Our results showed that treatment by relatively low concentrations (10-30 ?M) of deferoxamine (DFx), a natural iron-specific chelator, almost completely shielded the cells from BSO-induced toxicity and that DFx still remained protective when added up to 9-12h after BSO treatment. On the other hand, phosphopeptides derived from milk casein and known to carry iron across cell membranes, markedly potentiated the toxic action of BSO when loaded with iron but were ineffective in sodium form. Kept for 24 h in serum-free medium, the cells underwent a decrease in glutathione content after BSO treatment, but remained viable. However, these BSO-pre-treated cells showed a rapid (90-120 min) decrease in cell viability when incubated with low doses of iron, whereas a great proportion of them remained viable in the presence of higher concentrations of copper and zinc. We also observed in PC 12 cells an early (4-8 h) and transient increase in the expression of ferritin subunits following BSO addition. Taken together these results suggest that BSO-induced glutathione depletion leads to an alteration of cellular iron homeostasis, which may contribute to its toxicity. PMID:23680049

Chouraqui, E; Leon, A; Repesse, Y; Prigent-Tessier, A; Bouhallab, S; Bougle, D; Marie, C; Duval, D

2013-05-13

215

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

PubMed Central

High doses of intravenous desferrioxamine infused over a short period of time induce a large faecal and urinary iron excretion but also produce retinal abnormalities that are characterised by decreased amplitude on electroretinography and defective dark adaptation. This regimen also results in high faecal iron, zinc, and copper excretion, and reduced granulocyte zinc concentrations and alkaline phosphatase activity. The retinal abnormalities may be related to the zinc and copper deficiency and/or iron depletion 'per se' which interferes negatively with critical iron dependent enzymes.

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

1988-01-01

216

Satellite cell depletion does not inhibit adult skeletal muscle regrowth following unloading-induced atrophy  

PubMed Central

Resident muscle stem cells, known as satellite cells, are thought to be the main mediators of skeletal muscle plasticity. Satellite cells are activated, replicate, and fuse into existing muscle fibers in response to both muscle injury and mechanical load. It is generally well-accepted that satellite cells participate in postnatal growth, hypertrophy, and muscle regeneration following injury; however, their role in muscle regrowth following an atrophic stimulus remains equivocal. The current study employed a genetic mouse model (Pax7-DTA) that allowed for the effective depletion of >90% of satellite cells in adult muscle upon the administration of tamoxifen. Vehicle and tamoxifen-treated young adult female mice were either hindlimb suspended for 14 days to induce muscle atrophy or hindlimb suspended for 14 days followed by 14 days of reloading to allow regrowth, or they remained ambulatory for the duration of the experimental protocol. Additionally, 5-bromo-2?-deoxyuridine (BrdU) was added to the drinking water to track cell proliferation. Soleus muscle atrophy, as measured by whole muscle wet weight, fiber cross-sectional area, and single-fiber width, occurred in response to suspension and did not differ between satellite cell-depleted and control muscles. Furthermore, the depletion of satellite cells did not attenuate muscle mass or force recovery during the 14-day reloading period, suggesting that satellite cells are not required for muscle regrowth. Myonuclear number was not altered during either the suspension or the reloading period in soleus muscle fibers from vehicle-treated or satellite cell-depleted animals. Thus, myonuclear domain size was reduced following suspension due to decreased cytoplasmic volume and was completely restored following reloading, independent of the presence of satellite cells. These results provide convincing evidence that satellite cells are not required for muscle regrowth following atrophy and that, instead, the myonuclear domain size changes as myofibers adapt.

Jackson, Janna R.; Mula, Jyothi; Kirby, Tyler J.; Fry, Christopher S.; Lee, Jonah D.; Ubele, Margo F.; Campbell, Kenneth S.; McCarthy, John J.; Peterson, Charlotte A.

2012-01-01

217

Satellite cell depletion does not inhibit adult skeletal muscle regrowth following unloading-induced atrophy.  

PubMed

Resident muscle stem cells, known as satellite cells, are thought to be the main mediators of skeletal muscle plasticity. Satellite cells are activated, replicate, and fuse into existing muscle fibers in response to both muscle injury and mechanical load. It is generally well-accepted that satellite cells participate in postnatal growth, hypertrophy, and muscle regeneration following injury; however, their role in muscle regrowth following an atrophic stimulus remains equivocal. The current study employed a genetic mouse model (Pax7-DTA) that allowed for the effective depletion of >90% of satellite cells in adult muscle upon the administration of tamoxifen. Vehicle and tamoxifen-treated young adult female mice were either hindlimb suspended for 14 days to induce muscle atrophy or hindlimb suspended for 14 days followed by 14 days of reloading to allow regrowth, or they remained ambulatory for the duration of the experimental protocol. Additionally, 5-bromo-2'-deoxyuridine (BrdU) was added to the drinking water to track cell proliferation. Soleus muscle atrophy, as measured by whole muscle wet weight, fiber cross-sectional area, and single-fiber width, occurred in response to suspension and did not differ between satellite cell-depleted and control muscles. Furthermore, the depletion of satellite cells did not attenuate muscle mass or force recovery during the 14-day reloading period, suggesting that satellite cells are not required for muscle regrowth. Myonuclear number was not altered during either the suspension or the reloading period in soleus muscle fibers from vehicle-treated or satellite cell-depleted animals. Thus, myonuclear domain size was reduced following suspension due to decreased cytoplasmic volume and was completely restored following reloading, independent of the presence of satellite cells. These results provide convincing evidence that satellite cells are not required for muscle regrowth following atrophy and that, instead, the myonuclear domain size changes as myofibers adapt. PMID:22895262

Jackson, Janna R; Mula, Jyothi; Kirby, Tyler J; Fry, Christopher S; Lee, Jonah D; Ubele, Margo F; Campbell, Kenneth S; McCarthy, John J; Peterson, Charlotte A; Dupont-Versteegden, Esther E

2012-08-15

218

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

219

Differential effects of selective adenosine A 1 and A 2A receptor agonists on dopamine receptor agonist-induced behavioural responses in rats  

Microsoft Academic Search

The effects of the systemic (i.p.) administration of the selective adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and the selective adenosine A2A receptor agonist sodium 2-p-carboxyethyl)phenylamino-5?-N-carboxamidoadenosine (CGS 21680) on different dopamine receptor agonist-induced behaviours were studied in the male rat. CGS 21680 (1 ?mol\\/kg), but not CPA, was found to counteract the stereotypies induced by the non-selective dopamine receptor agonist apomorphine

Roberto Rimondini; Sergi Ferré; Lydia Giménez-Llort; Sven Ove Ögren; Kjell Fuxe

1998-01-01

220

A role for adenosine A 1 receptor blockade in the ability of caffeine to promote MDMA “Ecstasy”-induced striatal dopamine release  

Microsoft Academic Search

Co-administration of caffeine profoundly enhances the acute toxicity of 3,4 methylenedioxymethamphetamine (MDMA) in rats. The aim of this study was to determine the ability of caffeine to impact upon MDMA-induced dopamine release in superfused brain tissue slices as a contributing factor to this drug interaction. MDMA (100 and 300?M) induced a dose-dependent increase in dopamine release in striatal and hypothalamic

Natacha Vanattou-Saïfoudine; Anna Gossen; Andrew Harkin

2011-01-01

221

Individual Differences in Frontal Cortical Thickness Correlate with the d-Amphetamine-Induced Striatal Dopamine Response in Humans.  

PubMed

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

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

2013-09-18

222

Impact of dopamine versus serotonin cell transplantation for the development of graft-induced dyskinesia in a rat Parkinson model.  

PubMed

Graft-induced dyskinesia (GID), covering a range of dystonic and choreiform involuntary movements, has been observed in some patients with Parkinson's disease (PD) after intracerebral cell transplantation. These dyskinesias have been severe in a number of patients and represent one of the main obstacles for further development of the cell therapy in PD. Serotonin neurons, included into the dopaminergic cell suspension due to the nature of the dissection process, have been suggested as a key factor for the development of GID, since the administration of the serotonin (5-HT)(1A)-receptor agonist buspirone reduced dyskinesia in transplanted PD patients. In the present study, we characterized GID in the rat PD model after transplantation of dopaminergic grafts containing different amounts of serotonin neurons. The severity of GID was significantly correlated with the amount of grafted dopamine and serotonin neurons, but the r-values were low. However, neither the innervation density of dopamine and serotonin fibers in the grafted striatum nor the dopamine-to-serotonin cell ratio correlated significantly with the severity of GID. The results extend prior knowledge of the role of dopaminergic grafts in the development of GID and show that, in the animal model, serotonin neurons within the graft suspension might be involved, but given sufficient dopamine cells, their impact on GID may be minor. PMID:22759908

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

2012-07-01

223

Stress-Induced Sensitization and Glucocorticoids. I. Sensitization of Dopamine-Dependent Locomotor Effects of Amphetamine and Morphine Depends on Stress-Induced Corticosterone Secretion  

Microsoft Academic Search

Repeated exposures to stress sensitize motor and addic- tive effects of drugs of abuse. Recently, it has been shown that stress-induced behavioral sensitization depends on the secretion of glucocorticoids. We investigated if sensi- tization of dopamine-dependent effects of psychostimu- lants and opioids was influenced by glucocorticoids. Sen- sitization of the dopaminergic response to drugs is consid- ered the neural substrate

Vkronique Deroche; Michela Marinelli; Stefania Maccari; Pier Vincenzo Piazza

224

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

225

In vivo evidence of D 3 dopamine receptor sensitization in parkinsonian primates and rodents with l-DOPA-induced dyskinesias  

Microsoft Academic Search

A growing body of evidence indicates a role for D3 receptors in l-DOPA-induced dyskinesias. This involvement could be amenable to non-invasive in vivo analysis using functional neuroimaging. With this goal, we examined the hemodynamic response to the dopamine D3-preferring agonist 7-hydroxy-N,N-di-n-propyl-2 aminotetralin (7-OHDPAT) in naïve, parkinsonian and l-DOPA-treated, dyskinetic rodents and primates using pharmacological MRI (phMRI) and relative cerebral blood

Rosario Sánchez-Pernaute; Bruce G. Jenkins; Ji-Kyung Choi; Yin-Ching Iris Chen; Ole Isacsona

2007-01-01

226

Dopamine D 3 receptor stimulation underlies the development of L-DOPA-induced dyskinesia in animal models of Parkinson's disease  

Microsoft Academic Search

Development of L-DOPA-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson's disease (PD). Sensitization to L-DOPA correlates with ectopic expression of D3 dopamine receptors in the striatum, implicating D3 receptors in development of LID.We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP-lesioned marmosets without effecting the anti-parkinsonian actions of

Naomi P. Visanji; Susan H. Fox; Tom Johnston; Gabriela Reyes; Mark J. Millan; Jonathan M. Brotchie

2009-01-01

227

Effect of acute and chronic olanzapine treatment on phencyclidine-induced behavioral sensitization in rats with neonatal dopamine loss  

Microsoft Academic Search

In agreement with previous work, adult rats given selective lesions to dopamine (DA)-containing neurons as neonates exhibited a greater behavioral sensitization to repeated phencyclidine (PCP) treatment in comparison to sham-lesioned controls. Acute administration of olanzapine (1–5 mg\\/kg ip) or clozapine (15 mg\\/kg ip) decreased sensitized PCP-induced activity in both lesioned and control animals. Acute haloperidol (0.5 mg\\/kg ip) had no

Sheryl S Moy; Alda Fernandes; Ying Qian; Dana J Rotella; Richard M Kostrewa; George R Breese

2004-01-01

228

Role of dopamine receptors in the dual effect of naloxone on quinpirole-induced yawning in morphine pretreated rats  

Microsoft Academic Search

The present study was undertaken to determine the state of sensitivity of dopamine D2\\/133 receptors involved in the mediation of yawning behaviour at various times following acute morphine administration to rats. Morphine (3.0 mg\\/kg, s.c.) induced a biphasic effect on locomotor activity: an initial inhibitory phase lasting for about 30 min was after about an hour followed by a phase

Alexander Zharkovsky; Jaana Moisio; Toomas Kivastik; Liisa Ahtee

1993-01-01

229

Effects of dopamine receptor agonist and antagonists on cholestasis-induced anxiolytic-like behaviors in rats.  

PubMed

Dysfunctions in the dopamine transmission system have been suggested to contribute to the pathogenesis of hepatic encephalopathy. In an experimental animal model, cholestasis induction through bile duct ligation may present several main pathological features of hepatic encephalopathy. Dopaminergic systems are shown to play pivotal roles in regulation of anxiety-like behaviors. The main bile duct in male Wistar rats, weighing 220-240 g, was ligated using two ligatures plus duct transection in between. Anxiety-like behaviors were measured using the elevated plus maze task. Cholestasis increased the open arm time percentage (%OAT), 13 but not 10 days after bile duct ligation, indicating an anxiolytic-like effect. Sole intraperitoneal injection of apomorphine (dopamine D1/D2 receptor agonist, 0.25 mg/kg), SCH23390 (dopamine D1 receptor antagonist, 0.005, 0.01 and 0.02 mg/kg) or sulpiride (dopamine D2 receptor antagonist, 0.125, 0.25 and 0.5 mg/kg) did not alter %OAT, open arm entries percentage (%OAE) and locomotor activity in the sham-operated rats. Meanwhile, the higher dose apomorphine (0.5 mg/kg) induced anxiolytic-like behaviors in this group. The subthreshold dose injection of SCH23390 or sulpiride, partially reversed the anxiolytic-like behaviors induced by cholestasis (13 days after bile duct ligation). On the other hand, subthreshold dose of apomorphine in cholestatic rats (10 days post bile duct ligation) induced anxiolytic-like effects which could be blocked by SCH23390 or sulpiride. The effective doses of above drugs did not alter locomotor activity, number of rearings, groomings and defections. These findings suggested that the dopaminergic system may potentially be involved in the modulation of cholestasis-induced anxiolytic-like behaviors in rats. PMID:23376414

Reza Zarrindast, Mohammad; Eslimi Esfahani, Delaram; Oryan, Shahrbano; Nasehi, Mohammad; Torabi Nami, Mohammad

2013-01-29

230

Excitatory amino acid receptor antagonists decrease hypoxia induced increase in extracellular dopamine in striatum of newborn piglets  

Microsoft Academic Search

The present study tested the hypothesis that the increase in extracellular striatal dopamine during hypoxia is least partly associated with activation of N-methyl-D-aspartate (NMDA) and\\/or non-NMDA excitatory amino acid receptors. Studies were performed in anesthetized and mechanically ventilated 2–3 days old piglets. Hypoxic insult was induced by decreasing the oxygen fraction in inspired gas (FiO2) from 22 to 7% for

Meng-Fai Kuo; Dekun Song; Stephanie Murphy; Maria Delivoria Papadopoulos; David F. Wilson; Anna Pastuszko

1998-01-01

231

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

PubMed

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

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

2013-08-09

232

Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals.  

PubMed

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 nonexocytotic 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 2 h. 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, nonelectrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sugar reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sugar-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 upregulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. PMID:23303926

Daberkow, D P; Brown, H D; Bunner, K D; Kraniotis, S A; Doellman, M A; Ragozzino, M E; Garris, P A; Roitman, M F

2013-01-01

233

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

234

Comparison of dopamine receptor antagonists on hyperlocomotion induced by cocaine, amphetamine, MK-801 and the dopamine D1 agonist C-APB in mice  

Microsoft Academic Search

Rationale: Direct or indirect stimulation of dopamine receptors increases locomotor activity in mice. Determining the role played by\\u000a D1 and D2 dopamine receptors in the mediation of this activity can be difficult due to the wide variety of experimental paradigms used\\u000a to investigate these phenomena. Objectives: This study set out to compare the role of selective antagonism of dopamine D1

M. F. O’Neill; Gillian Shaw

1999-01-01

235

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

2012-10-23

236

Stress-induced dopamine release in human medial prefrontal cortex-(18) F-Fallypride/PET study in healthy volunteers.  

PubMed

Background: In laboratory animals, environmental stressors markedly activate the mesocortical dopamine system. The present study tested whether this occurs in humans. Methods: The effects of a laboratory psychological stressor (Montreal Imaging Stress Task, MIST) on mesocortical dopamine release in healthy young adults (11 males, mean age ± SD, 20.6 ± 2.4 years) was measured using positron emission tomography and [(18) F]fallypride. Each subject was scanned in two separate days in counterbalanced order: one with the MIST and one with the control task. Binding potential (BPND ) maps of the whole brain were calculated for each scan, using a simplified reference tissue compartmental model. Then BPND was compared between subjects. Heart rate, galvanic skin response, and salivary cortisol level were measured during the scans. Results: The psychological stressor significantly decreased [(18) F]fallypride binding values in the dorsal part of the medial prefrontal cortex (dmPFC), corresponding to the rostal part of the cingulate motor zone. The greater the stress-induced decrease in [(18) F]fallypride binding in the dmPFC, the greater the stress-induced increases in heart rate. Conclusions: The present study provides evidence of stress-induced dopamine release in the mPFC in humans, in vivo. Synapse 67:821-830, 2013. © 2013 Wiley Periodicals, Inc. PMID:23939822

Nagano-Saito, Atsuko; Dagher, Alain; Booij, Linda; Gravel, Paul; Welfeld, Krzysztof; Casey, Kevin F; Leyton, Marco; Benkelfat, Chawki

2013-09-12

237

Calcium store depletion induces persistent perisomatic increases in the functional density of h channels in hippocampal pyramidal neurons  

PubMed Central

SUMMARY The regulation of intracellular calcium by the endoplasmic reticulum (ER) plays a critical role in neuronal function. While the consequences associated with depleting calcium from the ER have been studied in multiple systems, it is not known whether the intrinsic properties of a neuron change in response to such perturbations. In this study, we demonstrate that the depletion of calcium from the ER of hippocampal CA1 pyramidal neurons induces a persistent, perisomatic increase in the density of functional h channels resulting in a reduction in intrinsic excitability and an increase in the optimal response frequency. This form of intrinsic plasticity is dependent on the elevation of cytoplasmic calcium, inositol triphosphate receptors, store-operated calcium channels, and the protein kinase A pathway. We postulate that this form of depletion-induced intrinsic plasticity is a neuroprotective mechanism that reduces excitability after depletion of calcium stores triggered through altered network activity during pathological conditions.

Narayanan, Rishikesh; Dougherty, Kevin; Johnston, Daniel

2010-01-01

238

GS28 Protects Neuronal Cell Death Induced by Hydrogen Peroxide under Glutathione-Depleted Condition  

PubMed Central

Golgi SNAP receptor complex 1 (GS28) has been implicated in vesicular transport between intra-Golgi networks and between endoplasmic reticulum (ER) and Golgi. Additional role(s) of GS28 within cells have not been well characterized. We observed decreased expression of GS28 in rat ischemic hippocampus. In this study, we examined the role of GS28 and its molecular mechanisms in neuronal (SK-N-SH) cell death induced by hydrogen peroxide (H2O2). GS28 siRNA-transfected cells treated with H2O2 showed a significant increase in cytotoxicity under glutathione (GSH)-depleted conditions after pretreatment with buthionine sulfoximine, which corresponded to an increase of intracellular reactive oxygen species (ROS) in the cells. Pretreatment of GS28 siRNA-transfected cells with p38 chemical inhibitor significantly inhibited cytotoxicity; we also observed that p38 was activated in the cells by immunoblot analysis. We confirmed the role of p38 MAPK in cotransfected cells with GS28 siRNA and p38 siRNA in the cell viability assay, flow cytometry, and immunoblot. Involvement of apoptotic or autophagic processes in the cells was not shown in the cell viability, flow cytometry, and immunoblot analyses. However, pretreatment of the cells with necrostatin-1 completely inhibited H2O2-induced cytotoxicity, ROS generation, and p38 activation, indicating that the cell death is necroptotic. Collectively these data imply that H2O2 induces necroptotic cell death in the GS28 siRNA-transfected cells and that the necroptotic signals are mediated by sequential activations in RIP1/p38/ROS. Taken together, these results indicate that GS28 has a protective role in H2O2-induced necroptosis via inhibition of p38 MAPK in GSH-depleted neuronal cells.

Lee, Hwa Ok; Byun, Yu Jeong; Cho, Kyung-Ok; Kim, Seong Yun; Lee, Seong-Beom; Kim, Ho-Shik; Kwon, Oh-Joo

2011-01-01

239

Ribavirin-induced intracellular GTP depletion activates transcription elongation in coagulation factor VII gene expression.  

PubMed

Coagulation FVII (Factor VII) is a vitamin K-dependent glycoprotein synthesized in hepatocytes. It was reported previously that FVII gene (F7) expression was up-regulated by ribavirin treatment in hepatitis C virus-infected haemophilia patients; however, its precise mechanism is still unknown. In the present study, we investigated the molecular mechanism of ribavirin-induced up-regulation of F7 expression in HepG2 (human hepatoma cell line). We found that intracellular GTP depletion by ribavirin as well as other IMPDH (inosine-5'-monophosphate dehydrogenase) inhibitors, such as mycophenolic acid and 6-mercaptopurine, up-regulated F7 expression. FVII mRNA transcription was mainly enhanced by accelerated transcription elongation, which was mediated by the P-TEFb (positive-transcription elongation factor b) complex, rather than by promoter activation. Ribavirin unregulated ELL (eleven-nineteen lysine-rich leukaemia) 3 mRNA expression before F7 up-regulation. We observed that ribavirin enhanced ELL3 recruitment to F7, whereas knockdown of ELL3 diminished ribavirin-induced FVII mRNA up-regulation. Ribavirin also enhanced recruitment of CDK9 (cyclin-dependent kinase 9) and AFF4 to F7. These data suggest that ribavirin-induced intracellular GTP depletion recruits a super elongation complex containing P-TEFb, AFF4 and ELL3, to F7, and modulates FVII mRNA transcription elongation. Collectively, we have elucidated a basal mechanism for ribavirin-induced FVII mRNA up-regulation by acceleration of transcription elongation, which may be crucial in understanding its pleiotropic functions in vivo. PMID:23050902

Suzuki, Atsuo; Miyawaki, Yuhri; Okuyama, Eriko; Murata, Moe; Ando, Yumi; Kato, Io; Takagi, Yuki; Takagi, Akira; Murate, Takashi; Saito, Hidehiko; Kojima, Tetsuhito

2013-01-01

240

Mechanism of mitochondrial stress-induced resistance to apoptosis in mitochondrial DNA-depleted C2C12 myocytes  

Microsoft Academic Search

In this study, we show that partial mitochondrial DNA (mtDNA) depletion (mitochondrial stress) induces resistance to staurosporine (STP)-mediated apoptosis in C2C12 myoblasts. MtDNA-depleted cells show a 3–4-fold increased proapoptotic proteins (Bax, BAD and Bid), markedly increased antiapoptotic Bcl-2, and reduced processing of p21 Bid to active tBid. The protein levels and also the ability to undergo STP-mediated apoptosis were restored

G Biswas; H K Anandatheerthavarada; N G Avadhani

2005-01-01

241

Tamoxifen counteracts estradiol induced effects on striatal and hypophyseal dopamine receptors  

SciTech Connect

We investigated the ability of Tamoxifen (TAM), an antiestrogen drug, to counteract the modification induced by estrogens on dopamine (DA) receptors on striatum and on adenohypophysis of ovex female rats. Subacute treatment with 17..beta..-estradiol (E/sub 2/) at both low (0.1 ..mu..g/kg) and high (20 ..mu..g/kg) doses confirmed its ability to increase the number of striatal /sup 3/H-Spiperone (/sup 3/H-SPI) binding sites in a dose dependent manner. By contrast in the pituitary, only high doses of estrogen were effective in reducing the number of DA receptors. We treated ovex female rats for 15 days with TAM alone or associated with E/sub 2/, to see if these estrogenic effects could be suppressed by an antiestrogenic drug. TAM did not affect the number of striatal DA receptors, but significantly increased the adenohypophy-seal DA binding sites, without varying their affinity. No changes were observed in pituitary and striatal DA receptor density, even when TAM was injected in association with estradiol. In conclusions: TAM is able to counteract the effects estrogens have on DA receptors. However there is some evidence that it could influence the pituitary DA systems independently of it antiestrogenic activity.

Ferretti, C.; Blengio, M.; Ghi, P.; Racca, S.; Genazzani, E.; Portaleone, P.

1988-01-01

242

An angiogenic inhibitor, cyclic RGDfV, attenuates MPTP-induced dopamine neuron toxicity  

PubMed Central

We previously demonstrated that several dopamine (DA) neurotoxins produced punctate areas of FITC-labeled albumin (FITC-LA) leakage in the substantia nigra and striatum suggesting blood brain barrier (BBB) dysfunction. Further, this leakage was co-localized with ?v?3 integrin up-regulation, a marker for angiogenesis. This suggested that the FITC-LA leakage might have been a result of angiogenesis. To assess the possible role of angiogenesis in DA neuron loss, we treated mice with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and on the following day treated with cyRGDfV, a cyclic peptide that binds to integrin ?v?3 and prevents angiogenesis. Post-treatment for three days (b.i.d.) with cyRGDfV blocked the MPTP-induced upregulation of integrin ?3 immunoreactivity (a marker for angiogenesis), leakage of FITC-LA into brain parenchyma (a marker for BBB disruption) as well as the down regulation of Zona Occludin-1 (ZO-1; a marker for tight junction integrity). In addition, cyRGDfV also completely prevented tyrosine hydroxylase immunoreactive cell loss (a marker for DA neurons) and markedly attenuated the up-regulation of activated microglia (Iba1 cell counts and morphology). These data suggest that cyRGDfV, and perhaps other anti-angiogenic drugs, are neuroprotective following acute MPTP treatment and may suggest that compensatory angiogenesis and BBB dysfunction may contribute to inflammation and DA neuron loss.

Patel, Aditiben; Toia, Giuseppe V; Colletta, Kalea; Bradaric, Brinda Desai; Carvey, Paul M; Hendey, Bill

2011-01-01

243

An angiogenic inhibitor, cyclic RGDfV, attenuates MPTP-induced dopamine neuron toxicity.  

PubMed

We previously demonstrated that several dopamine (DA) neurotoxins produced punctate areas of FITC-labeled albumin (FITC-LA) leakage in the substantia nigra and striatum suggesting blood brain barrier (BBB) dysfunction. Further, this leakage was co-localized with ?v?3 integrin up-regulation, a marker for angiogenesis. This suggested that the FITC-LA leakage might have been a result of angiogenesis. To assess the possible role of angiogenesis in DA neuron loss, we treated mice with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and on the following day treated with cyRGDfV, a cyclic peptide that binds to integrin ?v?3 and prevents angiogenesis. Post-treatment for 3 days (b.i.d.) with cyRGDfV blocked the MPTP-induced upregulation of integrin ?3 immunoreactivity (a marker for angiogenesis), leakage of FITC-LA into brain parenchyma (a marker for BBB disruption) as well as the down regulation of Zona Occludin-1 (ZO-1; a marker for tight junction integrity). In addition, cyRGDfV also completely prevented tyrosine hydroxylase immunoreactive cell loss (a marker for DA neurons) and markedly attenuated the up-regulation of activated microglia (Iba1 cell counts and morphology). These data suggest that cyRGDfV, and perhaps other anti-angiogenic drugs, are neuroprotective following acute MPTP treatment and may suggest that compensatory angiogenesis and BBB dysfunction may contribute to inflammation and DA neuron loss. PMID:21703263

Patel, Aditiben; Toia, Giuseppe V; Colletta, Kalea; Bradaric, Brinda Desai; Carvey, Paul M; Hendey, Bill

2011-06-15

244

Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice  

PubMed Central

Background Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia. Methodology/Principal Findings Through the use of stereological counting methods, we observed a significant reduction (?20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigra (SN) were observed with both acute and chronic dosing of 10 mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-? in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing. Conclusion Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences.

Sadasivan, Shankar; Pond, Brooks B.; Pani, Amar K.; Qu, Chunxu; Jiao, Yun; Smeyne, Richard J.

2012-01-01

245

Oxygen concentration control of dopamine-induced high uniformity surface coating chemistry.  

PubMed

Material surface engineering has attracted great interest in important applications, including electronics, biomedicine, and membranes. More recently, dopamine has been widely exploited in solution-based chemistry to direct facile surface modification. However, unsolved questions remain about the chemical identity of the final products, their deposition kinetics and their binding mechanism. In particular, the dopamine oxidation reaction kinetics is a key to improving surface modification efficiency. Here, we demonstrate that high O(2) concentrations in the dopamine solution lead to highly homogeneous, thin layer deposition on any material surfaces via accelerated reaction kinetics, elucidated by Le Chatelier's principle toward dopamine oxidation steps in a Michael-addition reaction. As a result, highly uniform, ultra-smooth modified surfaces are achieved in much shorter deposition times. This finding provides new insights into the effect of reaction kinetics and molecular geometry on the uniformity of modifications for surface engineering techniques. PMID:23273315

Kim, Hyo Won; McCloskey, Bryan D; Choi, Tae Hwan; Lee, Changho; Kim, Min-Joung; Freeman, Benny D; Park, Ho Bum

2013-01-03

246

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

Microsoft Academic Search

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

Wynne K Schiffer; Jean Logan; Stephen L Dewey

2003-01-01

247

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

248

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

249

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

250

Experimental system to search for induced depletion of 108mAg  

NASA Astrophysics Data System (ADS)

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

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

2008-10-01

251

The Glial Activation Inhibitor AV411 Reduces Morphine-Induced Nucleus Accumbens Dopamine Release  

PubMed Central

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

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

2009-01-01

252

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

PubMed

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

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

2009-02-03

253

Dopamine mediates cocaine-induced conditioned taste aversions as demonstrated with cross-drug preexposure to GBR 12909.  

PubMed

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. PMID:22579912

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

2012-05-03

254

Inhibitory effects of d 2 agonists by striatal injection on excessive release of dopamine and hyperactivity induced by bay k 8644 in rats  

Microsoft Academic Search

We investigated by means of behavioral and neurochemical studies the effects of either D1 or D2 agonist on excessive dopamine release and hyperactivity induced by the microinjection of Bay K 8644, and an L-type Ca2+ channel stimulant, into the rat caudate putamen under a novel environmental condition. Hyperactivity (locomotor activity and rearing counts) and significant increases in extracellular dopamine levels

H Maruya; Y Watanabe; M Okita; G. F Lawlor; H Utsumi; T Niitsuma

2003-01-01

255

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

256

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

Microsoft Academic Search

We tested the hypothesis that dopamine contributes significantly to the hydroxyl radical (OH)-induced striatal neurotoxicity caused by 3-nitropropionic acid (3-NP) in a rat model of Huntington's disease. Dopamine (10–100?M) or 3-NP (10–1000?M) individually caused a significant increase in the generation of hydroxyl radical (OH) in the mitochondria, which was synergistically enhanced when the lowest dose of the neurotoxin (10?M) and

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

2009-01-01

257

D2 dopamine receptor subtype-mediated hyperactivity and amphetamine responses in a model of ADHD  

PubMed Central

Low doses of psychostimulants produce beneficial behavioral effects in ADHD patients but the mechanisms underlying the response are not understood. Here we use the hyperactive mouse mutant coloboma to identify D2-like dopamine receptor subtypes that mediate the hyperactivity and response to amphetamine; we have previously demonstrated that D1-like dopamine receptors are not involved. Targeted deletion of the D2, but not the D3 or the D4, dopamine receptor in coloboma mice eliminated the hyperactivity; depleting D2 dopamine receptors also restored the excess dopamine overflow that may drive the hyperactivity to normal concentrations. Similar to its effects on ADHD patients, amphetamine reduced the hyperactivity of coloboma mice. The D2 dopamine receptor-selective antagonist L-741,626, but not D3 or D4 dopamine receptor-selective antagonists, blocked the amphetamine-induced reduction in locomotor activity. Thus, the D2 dopamine receptor subtype mediates the both the hyperactivity and response to amphetamine, suggesting a specific target for novel therapeutics in ADHD.

Fan, Xueliang; Xu, Ming; Hess, Ellen J.

2009-01-01

258

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

2013-03-29

259

Cigarette Smoking Induces Overexpression of a Fat-Depleting Gene AZGP1 in the Human  

PubMed Central

Background: Smokers weigh less and have less body fat than nonsmokers. Increased body fat and weight gain are observed following smoking cessation. To assess a possible molecular mechanism underlying the inverse association between smoking and body weight, we hypothesized that smoking may induce the expression of a fat-depleting gene in the airway epithelium, the cell population that takes the brunt of the stress of cigarette smoke. Methods: To assess whether smoking up-regulates expression in the airway epithelium of genes associated with weight loss, microarray analysis was used to evaluate genes associated with fat depletion in large airway epithelial samples obtained by fiberoptic bronchoscopy from healthy smokers and healthy nonsmokers. As a candidate gene we further evaluated the expression of ?2-zinc-glycoprotein 1 (AZGP1), a soluble protein that stimulates lipolysis, induces a reduction in body fat in mice, is associated with the cachexia related to cancer, and is known to be expressed in secretory cells of lung epithelium. AZGP1 protein expression was assessed by Western analysis and localization in the large airway epithelium by immunohistochemistry. Results: Both microarray and TaqMan analysis demonstrated that AZGP1 messenger RNA levels were higher in the large airway epithelium of healthy smokers compared to healthy nonsmokers (p < 0.05, all comparisons). Western analysis of airway biopsy specimens from smokers compared with those from nonsmokers demonstrated up-regulation of AZGP1 at the protein level, and immunohistochemical analysis demonstrated up-regulation of AZGP1 in secretory as well as neuroendocrine cells of smokers. Conclusions: In the context that AZGP1 is involved in lipolysis and fat loss, its overexpression in the airway epithelium of chronic smokers may represent one mechanism for the weight difference in smokers vs nonsmokers.

Vanni, Holly; Kazeros, Angeliki; Wang, Rui; Harvey, Ben-Gary; Ferris, Barbara; De, Bishnu P.; Carolan, Brendan J.; Hubner, Ralf-Harto; O'Connor, Timothy P.; Crystal, Ronald G.

2009-01-01

260

Cardiomyocyte apoptosis induced by short-term diabetes requires mitochondrial GSH depletion.  

PubMed

Oxidative stress due to excessive reactive oxygen species (ROS) and depleted antioxidants such as glutathione (GSH) can give rise to apoptotic cell death in acutely diabetic hearts and lead to heart disease. At present, the source of these cardiac ROS or the subcellular site of cardiac GSH loss [i.e., cytosolic (cGSH) or mitochondrial (mGSH) GSH] has not been completely elucidated. With the use of rotenone (an inhibitor of the electron transport chain) to decrease the excessive ROS in acute streptozotocin (STZ)-induced diabetic rat heart, the mitochondrial origin of ROS was established. Furthermore, mitochondrial damage, as evidenced by loss of membrane potential, increases in oxidative stress, and reduction in mGSH was associated with increased apoptosis via increases in caspase-9 and -3 activities in acutely diabetic hearts. To validate the role of mGSH in regulating cardiac apoptosis, L-buthionine-sulfoximine (BSO; 10 mmol/kg ip), which blocks GSH synthesis, or diethyl maleate (DEM; 4 mmol/kg ip), which inactivates preformed GSH, was administered in diabetic rats for 4 days after STZ administration. Although both BSO and DEM lowered cGSH, they were ineffective in reducing mGSH or augmenting cardiomyocyte apoptosis. To circumvent the lack of mGSH depletion, BSO and DEM were coadministered in diabetic rats. In this setting, mGSH was undetectable and cardiac apoptosis was further aggravated compared with the untreated diabetic group. In a separate group, GSH supplementation induced a robust amplification of mGSH in diabetic rat hearts and prevented apoptosis. Our data suggest for the first time that mGSH is crucial for modulating the cell suicide program in short-term diabetic rat hearts. PMID:15805231

Ghosh, Sanjoy; Pulinilkunnil, Thomas; Yuen, Gloria; Kewalramani, Girish; An, Ding; Qi, Dake; Abrahani, Ashraf; Rodrigues, Brian

2005-04-01

261

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

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 D(2)/D(3) receptor radioligand [(11)C]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 both its associative and sensorimotor functional divisions. In the associative striatum, speech-induced dopamine release established a significant relationship with neural activity and influenced the left-hemispheric lateralization of striatal functional networks. In contrast, there were no significant effects of endogenous dopamine release on the lateralization of striatal structural networks. Our data provide the first evidence for endogenous dopamine release in the dorsal striatum during normal speaking and point to the possible mechanisms behind the modulatory influences of dopamine on the organization of functional brain circuits controlling normal human speech. PMID:23277111

Simonyan, Kristina; Herscovitch, Peter; Horwitz, Barry

2012-12-28

262

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

263

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

264

West Nile Virus Infection Induces Depletion of IFNAR1 Protein Levels  

PubMed Central

Abstract Productive virus infection requires evasion, inhibition, or subversion of innate immune responses. West Nile virus (WNV), a human pathogen that can cause symptomatic infections associated with meningitis and encephalitis, inhibits the interferon (IFN) signal transduction pathway by preventing phosphorylation of Janus kinases and STAT transcription factors. Inhibition of the IFN signal cascade abrogates activation of IFN-induced genes, thus attenuating an antiviral response. We investigated the mechanism responsible for this inhibition and found that WNV infection prevents accumulation of the IFN-? receptor subunit 1 (IFNAR1). The WNV-induced depletion of IFNAR1 was conserved across multiple cell types. Our results indicated that expression of WNV nonstructural proteins resulted in activated lysosomal and proteasomal protein degradation pathways independent of the unfolded protein response (UPR). Furthermore, WNV infection did not induce serine phosphorylation, a modification on IFNAR1 that precedes its natural turnover. These data demonstrate that WNV infection results in a reduction of IFNAR1 protein through a non-canonical protein degradation pathway, and may participate in the inhibition of the IFN response.

Crown, Rachel A.; Sohn, Ji A.; Seeger, Christoph

2011-01-01

265

Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy.  

PubMed

Recent studies have revealed the scientific basis for the use of intravenous (i.v.) vitamin C or ascorbic acid (ascorbate) in treating cancers, and raised the possibility of using i.v. ascorbate as a prooxidant anticancer therapy. Through the production of H2O2, pharmacologic ascorbate can induce some cancer cell death in vitro and inhibit a number of types of tumor growth in animal models. However, the mechanism of cell death triggered by ascorbate is not well understood. In this study, we investigated the cytotoxicity of pharmacological concentrations of ascorbate to human prostate cancer cells and the mechanisms involved. The results showed that ascorbate in the millimolar range induced cytotoxicity in five of the six tested prostate cancer cell lines. The IC50 values in the sensitive prostate cancer cells ranged from 1.9 to 3.5 mmol/l, concentrations clinically achievable with i.v. ascorbate use. All tested androgen-independent cells were sensitive to ascorbate treatment. The ascorbate-insensitive cell line LaPC4 is hormonally dependent. Whereas the reasons for sensitivity/resistance to ascorbate treatment need to be investigated further, cell death in sensitive cells was dependent on H2O2. Ascorbate treatment depleted ATP and induced autophagy in sensitive prostate cancer cells, resulting in cell death. Taken together with previous studies, high-dose ascorbate has the potential to be a novel treatment option to hormone-refractory prostate cancer. PMID:22205155

Chen, Ping; Yu, Jun; Chalmers, Brain; Drisko, Jeanne; Yang, Jun; Li, Benyi; Chen, Qi

2012-04-01

266

Drug-induced parkinsonism  

Microsoft Academic Search

Opinion statement  Drug-induced parkinsonism (DIP) is condition that mimics Parkinson’s disease. Characterized mainly by rigidity and bradykinesia,\\u000a it has less prominent tremor and gait instability. DIP is generally caused by lipophilic drugs that “block” dopamine D2 receptors\\u000a in the brain, although presynaptic dopamine depletion, false transmitters, mitochondrial respiratory chain dysfunction, and\\u000a overactivity in the ?-aminobutyric acid (GABA)ergic system or cholinomimetic action

Frandy Susatia; Hubert H. Fernandez

2009-01-01

267

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

PubMed Central

Preclinical data have shown that addition of the selective norepinephrine transporter (NET) inhibitor reboxetine increases the antipsychotic-like effect of the D2/3 antagonist raclopride and, in parallel, enhances cortical dopamine output. Subsequent clinical results suggested that adding reboxetine to stable treatments with various antipsychotic drugs (APDs) may improve positive, negative and depressive symptoms in schizophrenia. In this study, we investigated in rats the effects of adding reboxetine to the second-generation APD olanzapine on: (i) antipsychotic efficacy, using the conditioned avoidance response (CAR) test, (ii) extrapyramidal side effect (EPS) liability, using a catalepsy test, (iii) dopamine efflux in the medial prefrontal cortex and the nucleus accumbens, using in vivo microdialysis in freely moving animals and (iv) cortical N-methyl--aspartate (NMDA) receptor-mediated transmission, using intracellular electrophysiological recording in vitro. Reboxetine (6?mg/kg) enhanced the suppression of CAR induced by a suboptimal dose (1.25?mg/kg), but not an optimal (2.5?mg/kg) dose of olanzapine without any concomitant catalepsy. Addition of reboxetine to the low dose of olanzapine also markedly increased cortical dopamine outflow and facilitated prefrontal NMDA receptor-mediated transmission. Our data suggest that adjunctive treatment with a NET inhibitor may enhance the therapeutic effect of low-dose olanzapine in schizophrenia without increasing EPS liability and add an antidepressant action, thus in principle allowing for a dose reduction of olanzapine with a concomitant reduction of dose-related side effects, such as EPS and weight gain.

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

2010-01-01

268

Spatial learning and memory deficits induced by dopamine administration with decreased glutathione.  

PubMed

Administration of buthionine sulfoximine (BSO) selectively inhibits glutathione (GSH) biosynthesis and induces a GSH deficiency. Decreased GSH levels in the brain may result in less oxidative stress (OS) protection, because GSH contributes substantially to intracellular antioxidant defense. Under these conditions, administration of the pro-oxidant, dopamine (DA), which rapidly oxidizes to form reactive oxygen species, may increase OS. To test the cognitive behavioral consequences of decreased GSH, BSO (3.2 mg in 30 microliters, intracerebroventricularly) was administered to male Fischer 344 rats every other day for 4 days. In addition, DA (15 microliters of 500 microM) was administered every day [either 1 h after BSO (BSO + DA group) or 1 h before BSO (DA + BSO group), when given on the same day as BSO] and spatial learning and memory assessed (Morris water maze, six trials/day). BSO + DA rats, but not DA + BSO rats, demonstrated cognitive impairment compared to a vehicle group, as evidenced by increased latencies to find the hidden platform, particularly on the first trial each day. Also, the BSO + DA group utilized non-spatial strategies during the probe trials (swim with no platform): i.e., less time spent in the platform quadrant, fewer crossings and longer latencies to the previous platform location, and more time spent in the platform quadrant, fewer crossings and longer latencies to the previous platform location, and more time spent around the edge of the pool rather than in the platform zone. Therefore, the cognitive behavioral consequences of decreasing GSH brain levels with BSO in conjunction with DA administration depends on the order of administration. These findings are similar to those seen previously on rod and plank walking performance, as well as to those seen in aged rats, suggesting that the oxidation of DA coupled with a reduced capacity to respond to oxidative stress may be responsible for the induction of age-related cognitive deficits. PMID:9626569

Shukitt-Hale, B; Erat, S A; Joseph, J A

1998-05-01

269

Nucleus accumbens dopamine D? receptors regulate the expression of ethanol-induced behavioural sensitization.  

PubMed

Repeated ethanol administration may induce behavioural sensitization, defined as a progressive potentiation of locomotor stimulant effects. This process is associated with neuroadaptations in the mesolimbic pathway and the nucleus accumbens. The aim of the present study was to analyse dopamine D? receptor (D?R) participation in locomotor response to an agonist and an antagonist of the D?R in mice with different levels of sensitization to ethanol. In three separate experiments, mice received administrations of 2.2 g/kg ethanol or saline every other day for 10 d. According to their locomotor response on the last day, ethanol-treated animals were classified into two groups: sensitized or non-sensitized. After the treatment, mice were challenged with 4 or 8 mg/kg SKF-38393 (i.p.), a D?R agonist (expt 1); or with 0.01 or 0.1 mg/kg SCH-23390 (i.p.), a D?R antagonist, followed by 2.2 g/kg ethanol (i.p.) administration (expt 2). In expt 3, mice were challenged with intra-accumbens (intra-NAc) SKF-38393 (1 ?g/side, in 0.2 ?l), and with intra-NAc SCH-23390 (3 ?g/side, in 0.2 ?l) followed by 2.2 g/kg ethanol (i.p.). Although the i.p. administration of SKF-38393 did not affect the locomotion of mice, the intra-NAc administration of SKF-38393 significantly increased the locomotor activity in sensitized mice, suggesting that sensitized mice present functionally hyperresponsive D?Rs in the NAc. Both i.p. and intra-NAc administration of SCH-23390 blocked the expression of ethanol sensitization, suggesting that the activation of NAc D?Rs seems to be essential for the expression of ethanol sensitization. PMID:20426882

Abrahao, Karina Possa; Quadros, Isabel Marian Hartmann; Souza-Formigoni, Maria Lucia Oliveira

2010-04-29

270

Gastrin and d1 dopamine receptor interact to induce natriuresis and diuresis.  

PubMed

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

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

2013-09-09

271

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

PubMed Central

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

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

2009-01-01

272

Running wheel exercise ameliorates methamphetamine-induced damage to dopamine and serotonin terminals.  

PubMed

Repeated administration of methamphetamine (mAMPH) to rodents in a single-day "binge" produces long-lasting damage to dopaminergic and serotonergic terminals. Because previous research has demonstrated that physical activity can ameliorate nigrostriatal injury, this study investigated whether voluntary exercise in rats can alter the monoaminergic damage resulting from a neurotoxic mAMPH binge. Adult male rats were allowed constant access to running wheels or kept in nonwheel cages for three weeks, then given a binge dosing regimen of mAMPH or saline. The rats were returned to their original environments for three additional weeks post-mAMPH. [(125) I]RTI-55 binding and autoradiography was used to quantify dopamine transporters (DAT), and radioimmunocytochemistry was used to quantify striatal tyrosine hydroxylase (TH). Binge mAMPH treatment significantly reduced striatal DAT and TH in a regionally specific pattern; with greatest effects in ventral caudate-putamen (CP) and relative sparing of the nucleus accumbens septi (NAc). The effects of mAMPH on striatal DAT and TH were ameliorated in the running, compared to the sedentary, animals. Also, mAMPH was found to reduce [(125) I]RTI-55 binding to serotonin transporters (SERT) in frontoparietal cortex, and this too was significantly attenuated by exercise. Additional correlational analyses showed that the post-mAMPH running of individual animals predicted the amelioration of striatal DAT and TH as well as frontoparietal SERT. Overall, voluntary exercise significantly diminished mAMPH-induced forebrain monoaminergic damage. The significant correlations between post-mAMPH exercise and markers of monoaminergic terminal integrity provide novel evidence that voluntary exercise may exert beneficial effects on behavior in recovering mAMPH addicts. PMID:21953518

O'Dell, Steven J; Galvez, Bryan A; Ball, Alexander J; Marshall, John F

2011-11-03

273

Apoptosis-inducing neurotoxicity of dopamine and its metabolites via reactive quinone generation in neuroblastoma cells.  

PubMed

Neurotoxic properties of L-dopa and dopamine (DA)-related compounds were assessed in human neuroblastoma SH-SY5Y cells with reference to their structural relationship. L-Dopa and its metabolites containing two free hydroxyl residues on their benzene ring showed toxicity in the cell, which was prevented by superoxide dismutase (SOD) and reduced glutathione (GSH), but not by catalase. Furthermore, a synthetic derivative of DA, 3-hydroxy-4-methoxyphenethylamine (HMPE) containing methoxy residue at position 4 in the benzene ring, exerted partial cytotoxicity, which was not prevented by SOD, GSH or catalase. However, the metabolites containing methoxy residue at position 3 failed to show a toxic effect in the SH-SY5Y cells. Moreover, DA induced apoptotic cell death, which was observed by nuclear and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and measurement of caspase-3 activity; this compound up-regulated apoptotic factor p53 while down-regulating anti-apoptotic factor Bcl-2. In the cell-free in vitro electron spin resonance (ESR) spectrometry, DA possessing two hydroxyl groups showed generation of DA-semiquinone radicals, which were markedly prevented by addition of SOD or GSH but not by catalase. On the other hand, methylation of one of the hydroxyl residues on the benzene ring of DA converted DA to an unoxidizable compound (3-MT or HMPE), and caused it to lose the property to produce semiquinone radicals. It has been previously reported that SOD acting as a superoxide:semiquinone oxidoreductase prevents quinone formation, and that reduced GSH through forming a complex with DA-quinone prevents quinone binding to the thiol group of the intact protein. Therefore, the present results suggest that DA and its metabolites containing two hydroxyl residues exert cytotoxicity mainly due to generation of highly reactive quinones. PMID:12495814

Emdadul Haque, M; Asanuma, Masato; Higashi, Youichirou; Miyazaki, Ikuko; Tanaka, Ken-ichi; Ogawa, Norio

2003-01-01

274

Global depletion of dopamine using intracerebroventricular 6-hydroxydopamine injection disrupts normal circadian wheel-running patterns and PERIOD2 expression in the rat forebrain.  

PubMed

Normal circadian rhythms of behavior are disrupted in disorders involving the dopamine (DA) system, such as Parkinson's disease. We have reported previously using unilateral injections of the catecholamine toxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle that DA signaling regulates daily expression of the clock protein, PERIOD2 (PER2), in the dorsal striatum of the rat. In the present study, we made widespread lesions of DA fibers using large injections of 6-OHDA into the third ventricle to determine the involvement of DA in normal daily rhythms of wheel-running activity and PER2 patterns in the suprachiasmatic nucleus (SCN) and several regions of the limbic forebrain. Rats injected with 6-OHDA and housed in constant darkness were less active in the wheel and showed a disorganized pattern of activity in which wheel running was not confined to a specific phase over 24 h. The 6-OHDA injection had no effect on the daily PER2 pattern in the SCN, but blunted the normal rise in PER2 in the dorsal striatum. 6-OHDA also blunted PER2 expression in the periventricular nucleus of the hypothalamus, a region in which a daily PER2 pattern has not been previously reported in male rats, and in the oval nucleus of the bed nucleus of the stria terminalis, but not in the central nucleus of the amygdala. These results indicate that DA plays a prominent role in regulating circadian activity at both behavioral and molecular levels. PMID:21484443

Gravotta, Luciana; Gavrila, Alex M; Hood, Suzanne; Amir, Shimon

2011-04-12

275

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

PubMed Central

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

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

2010-01-01

276

Studies of the Biogenic Amine Transporters. 12. Identification of Novel Partial Inhibitors of Amphetamine-Induced Dopamine Release  

PubMed Central

Previous studies identified partial inhibitors and allosteric modulators of 5-HT ([5-amino-3-(3,4-dichlorophenyl)-1,2-dihydropyrido[3,4-b]pyrazin-7-yl]carbamic acid ethyl ester [SoRI-6238], 4-(2-[bis(4-fluorophenyl)methoxy]ethyl)-1-(2-trifluoromethyl-benzyl)-piperidine [TB-1-099]) and dopamine transporters N-(Diphenylmethyl)-2-phenyl-4-quinazolinamine, [SoRI-9804]). We report here the identification of three novel allosteric modulators of the dopamine transporter (N-(2,2-Diphenylethyl)-2-phenyl-4-quinazolinamine [SoRI-20040], N-(3,3-Diphenylpropyl)-2-phenyl-4-quinazolinamine [SoRI-20041], [4-Amino-6-[(diphenylmethyl)amino]-5-nitro-2-pyridinyl]carbamic acid ethyl ester, [SoRI-2827]). Membranes were prepared from HEK cells expressing the cloned human dopamine (hDAT) transporter. [125I]RTI-55 binding and other assays followed published procedures. SoRI-20040, SoRI-20041 and SoRI-2827 partially inhibited [125I]RTI-55 binding with EC50 values ranging from ?1.4 ?M to 3 ?M and EMAX values decreasing as the [125I]RTI-55 concentrations increased. All three compounds decreased the [125I]RTI-55 Bmax and increased the apparent Kd in a manner well described by a sigmoid dose-response curve. In dissociation rate experiments, SoRI-20040 (10 ?M) and SoRI-20041 (10 ?M), but not SoRI-2827 (10 ?M), slowed the dissociation of [125I]RTI-55 from hDAT by ?30%. Using rat brain synaptosomes, all three agents partially inhibited [3H]dopamine uptake with EC50 values ranging from 1.8 ?M to 3.1 ?M and decreased the VMAX value in a dose-dependent manner. SoRI-9804 and SoRI-20040 partially inhibited amphetamine-induced DAT-mediated release of [3H]MPP+ from rat caudate synaptosomes in a dose-dependent manner. Viewed collectively, we report several compounds that allosterically modulate hDAT binding and function, and identify novel partial inhibitors of amphetamine-induced dopamine release.

Pariser, Joseph J.; Partilla, John S.; Dersch, Christina M.; Ananthan, Subramaniam; Rothman, Richard B.

2008-01-01

277

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

2013-08-30

278

IL-10 and IL-4 in skin allograft survival induced by T-cell depletion plus deoxyspergualin.  

PubMed

The mechanisms mediating T-cell depletion plus 15-deoxyspergualin (DSG)-induced prolonged allograft survival or tolerance are uncertain. The purpose of this study is to evaluate the role of IL-4 and IL-10 in prolonged allograft survival induced by T-cell depletion plus DSG. MHC mismatched skin allograft transplantation was performed, using wild-type and three separate knockout (i.e., IL-4-/-, Stat6-/-, or IL-1-/ -) mice as recipients. Induction therapy consisted of T-cell depletion and or brief course of DSG. The data demonstrate that monotherapy with T-cell-depleting mAbs or DSG prolonged skin allograft survival, compared to controls, in wild-type Balb/c recipients [median survival time (MST) = 25 and 21 vs. 10 days, p < 0.007]. T-cell depletion plus DSG further augmented skin allograft survival in wild-type animals relative to monotherapy (MST = 35 days vs. 25 and 21 days, p < 0.006 vs. mAbs or DSG only), and was equally effective in IL-4-/- and Stat6-/- recipients. In contrast, combined therapy was no better than monotherapy in IL-10-/- animals (p > 0.05). Furthermore, skin allograft survival after combined therapy was shorter in IL-10-/- versus wild-type recipients (MST 20 and 41 days, respectively, p < 0.001). IL-4-mediated signaling through Stat6 is dispensable for prolonged allograft survival induced by T-cell depletion plus DSG. In contrast, IL-10 appears to be important for prolonged allograft survival induced by combined therapy in this model. PMID:18819259

Asiedu, Clement; Andrades, Patricio; Ray, Peter D; George, James F; Thomas, Judith M

2008-01-01

279

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

PubMed Central

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

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

2011-01-01

280

Involvement of dopamine receptors in binge methamphetamine-induced activation of endoplasmic reticulum and mitochondrial stress pathways.  

PubMed

Single large doses of methamphetamine (METH) cause endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D(1) receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D(1) and D(2) receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D(1) or D(2) receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58(IPK), in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins (HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D(2)-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors. PMID:22174933

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

2011-12-13

281

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

282

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

2013-06-03

283

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

284

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

2013-08-12

285

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

286

Methylphenidate Exposure Induces Dopamine Neuron Loss and Activation of Microglia in the Basal Ganglia of Mice  

Microsoft Academic Search

BackgroundMethylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria

Shankar Sadasivan; Brooks B. Pond; Amar K. Pani; Chunxu Qu; Yun Jiao; Richard J. Smeyne

2012-01-01

287

Running wheel exercise enhances recovery from nigrostriatal dopamine injury without inducing neuroprotection  

Microsoft Academic Search

Forced use of the forelimb contralateral to a unilateral injection of the dopaminergic neurotoxin 6-hydroxydopamine can promote recovery of motor function in that limb and can significantly decrease damage to dopamine terminals. The present study was conducted to determine (1) whether a form of voluntary exercise, wheel running, would improve motor performance in rats with such lesions, and (2) whether

S. J. O’Dell; N. B. Gross; A. N. Fricks; B. D. Casiano; T. B. Nguyen; J. F. Marshall

2007-01-01

288

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…

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

2012-01-01

289

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

290

Behavioural sensitization to a dopamine agonist is associated with reversal of stress-induced anhedonia  

Microsoft Academic Search

Chronic exposure to very mild unpredictable stress (CMS) has previously been found to reduce the consumption of palatable sweet solutions and to impair place preference conditioning; evidence has been presented that these effects may reflect a dysfunction of the mesolimbic dopamine system. In the present study, rats were subjected to CMS for a total of 9 weeks. CMS reduced the

Mariusz Papp; Paul Willner; Richard Muscat

1993-01-01

291

Caffeine Induces Dopamine and Glutamate Release in the Shell of the Nucleus Accumbens  

Microsoft Academic Search

An increase in the extracellular concentration of dopamine in the nucleus accumbens (NAc) is believed to be one of the main mechanisms involved in the rewarding and motor-activating properties of psychostimulants such as amphetamines and cocaine. Using in vivo microdialysis in freely moving rats, we demonstrate that systemic administration of behaviorally rele- vant doses of caffeine can preferentially increase extracellular

Marcello Solinas; Sergi Ferre; Zhi-Bing You; Marzena Karcz-Kubicha; Patrizia Popoli; Steven R. Goldberg

2002-01-01

292

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

Microsoft Academic Search

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

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

2012-01-01

293

Individual differences in sugar consumption predict amphetamine-induced dopamine overflow in nucleus accumbens  

Microsoft Academic Search

Rats exhibit individual differences in their consumption of sugar and in their response to amphetamine treatments. Intrinsic variation in the functioning of the mesolimbic dopamine system is one potential mechanism underlying the expression of these individual differences. The present experiment examined the relationship between sugar consumption and the dopaminergic response to amphetamine. In vivo microdialysis was used to assess amphetamine-stimulated

Terrence L. Sills; Jacqueline N. Crawley

1996-01-01

294

Endoplasmic Reticulum Stress as a Mediator of Neurotoxin-Induced Dopamine Neuron Death.  

National Technical Information Service (NTIS)

The molecular processes of programmed cell death (PCD) are important mediators of neural degeneration in Parkinson's disease (PD). The goal of this proposal is to examine in living animals the possible role of ER stress, a mediator of PCD, in dopamine neu...

R. E. Burke

2005-01-01

295

Endoplasmic Reticulum Stress as a Mediator of Neurotoxin-Induced Dopamine Neuron Death.  

National Technical Information Service (NTIS)

The molecular processes of programmed cell death (PCD) are important mediators of neural degeneration in Parkinson's disease (PD). The goal of this proposal is to examine in living animals the possible role of ER stress, a mediator of PCD, in dopamine neu...

R. E. Burke

2006-01-01

296

Endoplasmic Reticulum Stress as a Mediator of Neurotoxin-Induced Dopamine Neuron Death.  

National Technical Information Service (NTIS)

The molecular processes of programmed cell death (PCD) are important mediators of neural degeneration in Parkinson's disease (PD). The goal of this proposal is to examine in living animals the possible role of ER stress, a mediator of PCD, in dopamine neu...

R. E. Burke

2004-01-01

297

Endoplasmic Reticulum Stress as a Mediator of Neurotoxin-Induced Dopamine Neuron Death.  

National Technical Information Service (NTIS)

Programmed cell death (PCD) is an important mediator of neural degeneration in Parkinson's disease (PD). The goal of this proposal was to examine in vivo the possible role of endoplasmic recticulum (ER) stress, a mediator of PCD, in dopamine neuron death....

R. E. Burke

2007-01-01

298

Intratracheal dopamine attenuates pulmonary edema and improves survival after ventilator-induced lung injury in rats  

Microsoft Academic Search

INTODUCTION: Clearance of alveolar oedema depends on active transport of sodium across the alveolar-epithelial barrier. ?-Adrenergic agonists increase clearance of pulmonary oedema, but it has not been established whether ?-agonist stimulation achieves sufficient oedema clearance to improve survival in animals. The objective of this study was to determine whether the increased pulmonary oedema clearance produced by intratracheal dopamine improves the

Virginia Chamorro-Marín; Manuel García-Delgado; Angel Touma-Fernández; Eduardo Aguilar-Alonso; Enrique Fernández-Mondejar

2008-01-01

299

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

300

Eating induced rise in LHA-dopamine correlates with meal size in normal and bulbectomized rats.  

PubMed

Dopaminergic function in the lateral hypothalamic area (LHA) is important for processing intrinsic and extrinsic feeding related information. Brain microdialysis was used to examine if dopamine release in the LHA correlates with meal size in normal and bulbectomized rats. Food-deprived bulbectomized rats ate significantly less food (1.7 +/- 0.1 g) than food-deprived sham operated rats (3.1 +/- 0.5 g, p < 0.05), accompanied by a lesser increase in LHA-dopamine release (150.6 +/- 4.9% vs. 195.1 +/- 13.9, p < 0.02). LHA-dopamine release was significantly higher in rats which ate a full meal (2.9 +/- 0.1 g) than in rats which ate half a meal (1.5 +/- 0.1 g, p < 0.05), being 155.9 +/- 7.8% vs. 131.0 +/- 4.9% (p < 0.05) in food-deprived normal rats. Data suggest that dopamine release in the LHA correlates to the quantity of food consumed during a meal. PMID:7712212

Meguid, M M; Yang, Z J; Koseki, M

1995-01-01

301

Dopamine and serotonin release in the nucleus accumbens during starvation-induced hyperactivity  

Microsoft Academic Search

Activity-based anorexia (ABA) is considered an animal model for anorexia nervosa (AN). By scheduled feeding and voluntary wheel running, it mimics severe body weight loss and increased physical activity in AN. Pharmacological, genetic and imaging studies implicate dopamine and serotonin in the regulation of feeding behavior, food-anticipatory activity, and food reward. Previous studies propose that the nucleus accumbens (NAc) plays

Linda A. W. Verhagen; Mieneke C. M. Luijendijk; Gerdien A. H. Korte-Bouws; S. Mechiel Korte; Roger A. H. Adan

2009-01-01

302

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

303

Inhibition of calcium-induced insulin secretion from intact HIT-T15 or INS1 ? cells by GTP depletion  

Microsoft Academic Search

Using intact rat islets, we previously observed that GTP depletion (achieved through the use of mycophenolic acid or other synthesis inhibitors) impedes nutrient- but not K+-induced insulin secretion. It was concluded that a proximal nutrient-dependent step in stimulus-secretion coupling (but not the process of Ca2+-induced exocytosis itself) is modulated by ambient GTP levels. To examine Ca2+-dependent steps further in intact

Melissa Meredith; Guodong Li; Stewart A. Metz

1997-01-01

304

Inhibition of oestradiol-induced prolactin release in a dual-cannulated ovariectomized rat model by carmoxirole, a peripherally restricted dopamine agonist.  

PubMed

Centrally acting dopamine agonists (e.g. bromocriptine) and dopamine transport inhibitors (e.g. GBR12909) are known to inhibit oestradiol-induced prolactin release. The capacity of peripherally restricted compounds to do likewise, however, is unknown. Here, the effects of the peripherally restricted dopamine receptor agonist carmoxirole on oestradiol-induced prolactin release were investigated. Dual-cannulated ovariectomized rats were used, so that a robust, reproducible response to exogenous oestrogen could be induced and sequential blood samples were taken with minimal stress. Carmoxirole (15 mg/kg) inhibited oestradiol-induced prolactin release, similar to bromocriptine and GBR12909. However, carmoxirole also induced a rapid, transient, oestradiol-independent release of prolactin. These data show that peripherally restricted dopamine receptor agonists are sufficient to inhibit oestradiol-induced prolactin release. Like centrally acting compounds, they may therefore be expected to affect the incidence of prolactin-dependent tumours in rat carcinogenesis studies without inducing central-mediated side effects. PMID:22742711

Brott, David A; Werkheiser, Jennifer L; Campbell, Pam; Bentley, Patricia; Andersson, Håkan H A S; Stewart, Jane; Huby, Russell; Altekar, Maneesha; Kinter, Lewis B

2012-07-31

305

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

306

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

PubMed

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

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

2006-05-31

307

Role of cAMP Signaling in the Mediation of Dopamine-Induced Stimulation of GnRH Secretion via D1 Dopamine Receptors in GT1-7 Cells  

Microsoft Academic Search

Pharmacologically increasing cyclic adenosine monophosphate (cAMP) levels in GT1 gonadotropin-releasing hormone (GnRH) cell lines increased the secretion of GnRH. Dopamine (DA) increased the GnRH secretion in GT1 cells via a DA receptor positively coupled to adenylate cyclase. We then asked whether inhibition of the DA-induced increase in cAMP would block the stimulatory effect of DA on GnRH release. Expression of

Hiroshi Yoshida; Sreenivasan Paruthiyil; Paul Butler; Richard I. Weiner

2004-01-01

308

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

PubMed

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

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

2013-06-01

309

Noradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for Alzheimer's disease.  

PubMed

Degeneration of locus ceruleus (LC) neurons and reduced levels of norepinephrine (NE) in LC projection areas are well known features of Alzheimer's disease (AD); however, the consequences of those losses are not clear. Because inflammatory mediators contribute to AD pathogenesis and because NE can suppress inflammatory gene expression, we tested whether LC loss influenced the brain inflammatory gene expression elicited by amyloid beta (Abeta). Adult rats were injected with the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4) to induce LC death and subsequently injected in the cortex with Abeta (aggregated 1-42 peptide). DSP4 treatment potentiated the Abeta-dependent induction of inflammatory nitric oxide synthase (iNOS), interleukin (IL)-1beta, and IL-6 expression compared with control animals. In contrast, the induction of cyclooxygenase-2 expression was not modified by DSP4 treatment. In control animals, injection of Abeta induced iNOS primarily in microglial cells, whereas in DSP4-treated animals, iNOS was localized to neurons, as is observed in AD brains. Injection of Abeta increased IL-1beta expression initially in microglia and at later times in astrocytes, and expression levels were greater in DSP4-treated animals than in controls. The potentiating effects of DSP4 treatment on iNOS and IL-1beta expression were attenuated by coinjection with NE or the beta-adrenergic receptor agonist isoproterenol. These data demonstrate that LC loss and NE depletion augment inflammatory responses to Abeta and suggest that LC loss in AD is permissive for increased inflammation and neuronal cell death. PMID:11923407

Heneka, Michael T; Galea, Elena; Gavriluyk, Vitaliy; Dumitrescu-Ozimek, Lucia; Daeschner, JoAnna; O'Banion, M Kerry; Weinberg, Guy; Klockgether, Thomas; Feinstein, Douglas L

2002-04-01

310

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

311

Imaging D2 Receptor Occupancy by Endogenous Dopamine in Humans  

Microsoft Academic Search

The impact of endogenous dopamine on in vivo measurement of D2 receptors in humans was evaluated with single photon emission computerized tomography (SPECT), by comparing the binding potential (BP) of the selective D2 radiotracer [123I]IBZM before and after acute dopamine depletion. Dopamine depletion was achieved by administration of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT), given orally at a dose of

Marc Laruelle; Cyril D D’Souza; Ronald M Baldwin; Anissa Abi-Dargham; Stephen J Kanes; Christine L Fingado; John P Seibyl; Sami S Zoghbi; Malcolm B Bowers; Peter Jatlow; Dennis S Charney; Robert B Innis

1997-01-01

312

Effect of the Nigrostriatal Dopamine System on Acquired Neural Responses in the Striatum of Behaving Monkeys  

Microsoft Academic Search

Dysfunction of the nigrostriatal dopamine system results in marked disorders of movement such as occur in Parkinson's disease. Functions of this dopamine-containing projection system were examined in monkeys trained in a classical conditioning task, and the effects of striatal dopamine depletion were tested. Unilateral dopamine loss substantially reduced the acquired sensory responsiveness of striatal neurons monitored electrophysiologically. This effect was

Toshihiko Aosaki; Ann M. Graybiel; Minoru Kimura

1994-01-01

313

Differences in Nicotine-Induced Dopamine Release and Nicotine Pharmacokinetics Between Lewis and Fischer 344 Rats  

Microsoft Academic Search

Studies have shown a greater preference for the self-administration of drugs such as nicotine and cocaine in the Lewis rat strain than in the Fischer 344 strain. We examined some factors that could contribute to such a difference. The baseline level of extracellular dopamine in nucleus accumbens shell was about 3-times higher in Fischer rats than in Lewis rats (3.18

I. Sziraki; M. N. Lipovac; A. Hashim; H. Sershen; D. Allen; T. Cooper; P. Czobor; A. Lajtha

2001-01-01

314

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; Nisticò, R; Puglisi-Allegra, S; Mercuri, N B

2013-08-08

315

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

316

Stress-Induced Dopamine Release in Humans at Risk of Psychosis: a [11C]Raclopride PET Study  

Microsoft Academic Search

Drugs that increase dopamine levels in the brain can cause psychotic symptoms in healthy individuals and worsen them in schizophrenic patients. Psychological stress also increases dopamine release and is thought to play a role in susceptibility to psychotic illness. We hypothesized that healthy individuals at elevated risk of developing psychosis would show greater striatal dopamine release than controls in response

Alexandra Soliman; Gillian A O'Driscoll; Jens Pruessner; Anne-Lise V Holahan; Isabelle Boileau; Danny Gagnon; Alain Dagher

2008-01-01

317

Decreased ER-associated degradation of ?-TCR induced by Grp78 depletion with the SubAB cytotoxin  

PubMed Central

HeLa cells stably expressing the ? chain of T-cell receptor (?TCR), a model substrate of ERAD (ER-associated degradation), were used to analyze the effects of BiP/Grp78 depletion by the SubAB cytotoxin. SubAB induced XBP1 splicing, followed by JNK phosphorylation, eIF2? phosphorylation, upregulation of ATF3/4 and partial ATF6 cleavage. Other markers of ER stress, including elements of ER-associated degradation (ERAD) pathway, as well as markers of cytoplasmic stress, were not induced. SubAB treatment decreased absolute levels of ?TCR, which was caused by inhibition of protein synthesis. At the same time, the half-life of ?TCR was extended almost fourfold from 70 min to 210 min, suggesting that BiP normally facilitates ERAD. Depletion ofp97/VCP partially rescued SubAB-induced depletion of ?TCR, confirming the role of VCP in ERAD of ?TCR. It therefore appears that ERAD of ?TCR is driven by at least two different ATP-ase systems located at two sides of the ER membrane, BiP located on the lumenal side, while p97/VCP on the cytoplasmic side. While SubAB altered cell morphology by inducing cytoplasm vacuolization and accumulation of lipid droplets, caspase activation was partial and subsided after prolonged incubation. Expression of CHOP/GADD153 occurred only after prolonged incubation and was not associated with apoptosis.

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

2008-01-01

318

AGE-DEPENDENT EFFECTS OF ?-OPIOID RECEPTOR STIMULATION ON COCAINE-INDUCED STEREOTYPED BEHAVIORS AND DOPAMINE OVERFLOW IN THE CAUDATE-PUTAMEN: AN IN VIVO MICRODIALYSIS STUDY  

PubMed Central

?-Opioid receptor stimulation attenuates psychostimulant-induced increases in extracellular dopamine in the caudate-putamen (CPu) and nucleus accumbens of adult rats, while reducing cocaine-induced locomotor activity and stereotyped behaviors. Because ?-opioid receptor agonists (e.g., U50,488 or U69,593) often affect the behavior of preweanling rats in a paradoxical manner, the purpose of the present study was to determine whether ?-opioid receptor stimulation differentially affects dopaminergic functioning in the CPu depending on age. In vivo microdialysis was used to determine whether U50,488 (5 mg/kg) attenuates cocaine-induced dopamine overflow in the dorsal CPu on postnatal day (PD) 17 and PD 85. In the microinjection experiment, cocaine-induced stereotyped behaviors were assessed in adult and preweanling rats after bilateral infusions of vehicle or U50,488 (1.6 or 6.4 µg per side) into the CPu. Results showed that U50,488 attenuated the cocaine-induced increases in CPu dopamine overflow on PD 85, while the same dose of U50,488 did not alter dopamine dialysate levels on PD 17. Cocaine also increased stereotyped behaviors (repetitive motor movements, behavioral intensity scores, and discrete behaviors) at both ages, but adult rats appeared to exhibit more intense stereotypic responses than the younger animals. Consistent with the microdialysis findings, bilateral infusions of U50,488 into the dorsal CPu decreased the cocaine-induced stereotypies of adult rats, while leaving the behaviors of preweanling rats unaffected. These results suggest that the neural mechanisms underlying ?-opioid/dopamine interactions in the CPu are not fully mature during the preweanling period. This lack of functional maturity may explain why ?-opioid receptor agonists frequently induce different behavioral effects in young and adult rats.

Cortez, A. M.; Charntikov, S.; Der-Ghazarian, T.; Horn, L. R.; Crawford, C. A.; McDougall, S. A.

2010-01-01

319

Dopamine D-2 antagonists reverse apomorphine-induced decreased water intake in the rat: prediction of antipsychotic drugs with few extrapyramidal side-effects?  

Microsoft Academic Search

Summary Water intake in water deprived rats was decreased by administration of a low dose of apomorphine (0.1 mg\\/kg s.c.). This dose is too low to induce hyperactivity and stereotypies. Four different dopamine (DA) D-2 antagonists were used to counteract this effect of apomorphine; haloperidol [an antipsychotic inducing extrapyramidal side-effects (EPS)], sulpiride (an antipsychotic inducing less EPS than haloperidol), metoclopramide

T. Ljungberg

1989-01-01

320

Caffeine promotes dopamine D 1 receptor-mediated body temperature, heart rate and behavioural responses to MDMA (‘ecstasy’)  

Microsoft Academic Search

Rationale  Caffeine exacerbates the acute toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) in rats characterised by hyperthermia,\\u000a tachycardia and lethality. Depletion of central catecholamine stores and dopamine D1 receptor blockade have been reported to attenuate the ability of caffeine to exacerbate MDMA-induced hyperthermia.\\u000a \\u000a \\u000a \\u000a \\u000a Objectives  Here, we investigate whether dopamine D1 and D2 receptors mediate the effects of caffeine on MDMA-induced changes in body temperature,

Natacha Vanattou-Saïfoudine; Ruth McNamara; Andrew Harkin

2010-01-01

321

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

Microsoft Academic Search

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

Rueben A. Gonzales; Friedbert Weiss

322

Dopamine triggers Heterosynaptic Plasticity  

PubMed Central

As a classic neuromodulator, dopamine has long been thought to modulate, rather than trigger, synaptic plasticity. In contrast, our present results demonstrate that within the parallel projections of dopaminergic and GABAergic terminals from the ventral tegmental area (VTA) to nucleus accumbens core (NAcCo), action potential-activated release of dopamine heterosynaptically triggers LTD at GABAergic synapses, which is likely mediated by activating presynaptically-located dopamine D1 class receptors and expressed by inhibiting presynaptic release of GABA. Moreover, this dopamine-mediated heterosynaptic LTD is abolished after withdrawal from cocaine exposure. These results suggest that action potential-dependent dopamine release triggers very different cellular consequences from those induced by volume release or pharmacological manipulation. Activation of the VTA-to-NAcCo projections is essential for emotional and motivational responses. This dopamine-mediated LTD allows a flexible output of NAcCo neurons, whereas disruption of this LTD may contribute to the rigid emotional and motivational state observed in addicts during cocaine withdrawal.

Ishikawa, Masago; Otaka, Mami; Huang, Yanhua; Neumann, Peter A.; Winters, Bradley D.; Grace, Anthony A.; Schluter, Oliver M.; Dong, Yan

2013-01-01

323

Dopamine triggers heterosynaptic plasticity.  

PubMed

As a classic neuromodulator, dopamine has long been thought to modulate, rather than trigger, synaptic plasticity. In contrast, our present results demonstrate that within the parallel projections of dopaminergic and GABAergic terminals from the ventral tegmental area to the nucleus accumbens core (NAcCo), action-potential-activated release of dopamine heterosynaptically triggers LTD at GABAergic synapses, which is likely mediated by activating presynaptically located dopamine D1 class receptors and expressed by inhibiting presynaptic release of GABA. Moreover, this dopamine-mediated heterosynaptic LTD is abolished after withdrawal from cocaine exposure. These results suggest that action-potential-dependent dopamine release triggers very different cellular consequences from those induced by volume release or pharmacological manipulation. Activation of the ventral tegmental area to NAcCo projections is essential for emotional and motivational responses. This dopamine-mediated LTD allows a flexible output of NAcCo neurons, whereas disruption of this LTD may contribute to the rigid emotional and motivational state observed in addicts during cocaine withdrawal. PMID:23595734

Ishikawa, Masago; Otaka, Mami; Huang, Yanhua H; Neumann, Peter A; Winters, Bradley D; Grace, Anthony A; Schlüter, Oliver M; Dong, Yan

2013-04-17

324

Depletion of intracellular Ca2+ stores enhances flow-induced vascular dilatation in rat small mesenteric artery  

PubMed Central

The effect of depleting intracellular Ca2+ stores on flow-induced vascular dilatation and the mechanism responsible for the vasodilatation were examined in rat isolated small mesenteric arteries. The arteries were pressurized to 50?mmHg and preconstricted with phenylephrine. Intraluminal flow reversed the effect of phenylephrine, resulting in vasodilatation. Flow dilatation consisted of an initial transient peak followed by a sustained plateau phase. The magnitude of dilatation was markedly reduced by removing Ca2+ from the intraluminal flow medium. Depletion of intracellular Ca2+ stores with either cyclopiazonic acid (CPA, 2??M) or 1,4-dihydroxy-2,5-di-tert-butylbenzene (BHQ, 10??M) significantly augmented the magnitude of flow dilatation. Flow-induced endothelial cell Ca2+ influx was also markedly enhanced in arteries pretreated with CPA or BHQ. Flow-induced dilatation was insensitive to Nw-nitro-L-arginine methyl ester (100??M) plus indomethacin (3??M) or to oxyhemoglobin (3??M), but was markedly reduced by 30?mM extracellular K+ or 2?mM tetrabutylammonium (TBA), suggesting an involvement of EDHF. Catalase at 1200?U?ml?1 abolished the flow-induced dilatation, while the application of exogenous H2O2 (90–220??M) induced relaxation in phenylephrine-preconstricted arteries. Relaxation to exogenous H2O2 was blocked in the presence of 30?mM extracellular K+, and H2O2 (90??M) hyperpolarized the smooth muscle cells, indicating that H2O2 can act as an EDHF. In conclusion, flow-induced dilatation in rat mesenteric arteries can be markedly enhanced by prior depletion of intracellular Ca2+ stores. Furthermore, these data are consistent with a role for H2O2 as the vasodilator involved.

Liu, Cuiling; Ngai, Ching-Yuen; Huang, Yu; Ko, Wing-Hung; Wu, Min; He, Guo-Wei; Garland, Christopher J; Dora, Kim A; Yao, Xiaoqiang

2006-01-01

325

Depletion of HPV16 early genes induces autophagy and senescence in a cervical carcinogenesis model, regardless of viral physical state.  

PubMed

In cervical carcinomas, high-risk human papillomavirus (HR-HPV) may be integrated into host chromosomes or remain extra-chromosomal (episomal). We used the W12 cervical keratinocyte model to investigate the effects of HPV16 early gene depletion on in vitro cervical carcinogenesis pathways, particularly effects shared by cells with episomal versus integrated HPV16 DNA. Importantly, we were able to study the specific cellular consequences of viral gene depletion by using short interfering RNAs known not to cause phenotypic or transcriptional off-target effects in keratinocytes. We found that while cervical neoplastic progression in vitro was characterized by dynamic changes in HPV16 transcript levels, viral early gene expression was required for cell survival at all stages of carcinogenesis, regardless of viral physical state, levels of early gene expression or histology in organotypic tissue culture. Moreover, HPV16 early gene depletion induced changes in host gene expression that were common to both episome-containing and integrant-containing cells. In particular, we observed up-regulation of autophagy genes, associated with enrichment of senescence and innate immune-response pathways, including the senescence-associated secretory phenotype (SASP). In keeping with these observations, HPV16 early gene depletion induced autophagy in both episome-containing and integrant-containing W12 cells, as evidenced by the appearance of autophagosomes, punctate expression of the autophagy marker LC3, conversion of LC3B-I to LC3B-II, and reduced levels of the autophagy substrate p62. Consistent with the reported association between autophagy and senescence pathways, HPV16 early gene depletion induced expression of the senescence marker beta-galactosidase and increased secretion of the SASP-related protein IGFBP3. Together, these data indicate that depleting HR-HPV early genes would be of potential therapeutic benefit in all cervical carcinogenesis pathways, regardless of viral physical state. In addition, the senescence/SASP response associated with autophagy induction may promote beneficial immune effects in bystander cells. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:23913724

Hanning, Jennifer E; Saini, Harpreet K; Murray, Matthew J; Caffarel, Maria M; van Dongen, Stijn; Ward, Dawn; Barker, Emily M; Scarpini, Cinzia G; Groves, Ian J; Stanley, Margaret A; Enright, Anton J; Pett, Mark R; Coleman, Nicholas

2013-11-01

326

VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation.  

PubMed

The "One neuron-one neurotransmitter" concept has been challenged frequently during the last three decades, and the coexistence of neurotransmitters in individual neurons is now regarded as a common phenomenon. The functional significance of neurotransmitter coexistence is, however, less well understood. Several studies have shown that a subpopulation of dopamine (DA) neurons in the ventral tegmental area (VTA) expresses the vesicular glutamate transporter 2 (VGLUT2) and has been suggested to use glutamate as a cotransmitter. The VTA dopamine neurons project to limbic structures including the nucleus accumbens, and are involved in mediating the motivational and locomotor activating effects of psychostimulants. To determine the functional role of glutamate cotransmission by these neurons, we deleted VGLUT2 in DA neurons by using a conditional gene-targeting approach in mice. A DAT-Cre/Vglut2Lox mouse line (Vglut2(f/f;DAT-Cre) mice) was produced and analyzed by in vivo amperometry as well as by several behavioral paradigms. Although basal motor function was normal in the Vglut2(f/f;DAT-Cre) mice, their risk-taking behavior was altered. Interestingly, in both home-cage and novel environments, the gene targeted mice showed a greatly blunted locomotor response to the psychostimulant amphetamine, which acts via the midbrain DA system. Our results show that VGLUT2 expression in DA neurons is required for normal emotional reactivity as well as for psychostimulant-mediated behavioral activation. PMID:20018672

Birgner, Carolina; Nordenankar, Karin; Lundblad, Martin; Mendez, José Alfredo; Smith, Casey; le Grevès, Madeleine; Galter, Dagmar; Olson, Lars; Fredriksson, Anders; Trudeau, Louis-Eric; Kullander, Klas; Wallén-Mackenzie, Asa

2009-12-14

327

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

328

Hepatic transcriptome and proteome responses against diethyl maleate-induced glutathione depletion in the rat  

Microsoft Academic Search

Hepatic transcriptome and proteome responses against glutathione depletion were investigated by Affymetrix GeneChip Microarray\\u000a and 2-dimensional gel electrophoresis (2D-DIGE), followed by MALDI-TOF–MS analysis and utilizing a glutathione-depleted rat\\u000a model treated with diethyl maleate (DEM). Hepatic glutathione content decreased to 1.29 ?mol\\/g liver (25.5% compared to control)\\u000a after DEM treatment, and there were no apparent hepatotoxic signs estimated by blood chemistry examinations.

Shusuke Yamauchi; Naoki Kiyosawa; Yosuke Ando; Kyoko Watanabe; Noriyo Niino; Kazumi Ito; Takashi Yamoto; Sunao Manabe; Atsushi Sanbuissho

329

Impact of dendritic spine preservation in medium spiny neurons on dopamine graft efficacy and the expression of dyskinesias in parkinsonian rats.  

PubMed

Dopamine deficiency associated with Parkinson's disease (PD) results in numerous changes in striatal transmitter function and neuron morphology. Specifically, there is marked atrophy of dendrites and dendritic spines on striatal medium spiny neurons (MSN), primary targets of inputs from nigral dopamine and cortical glutamate neurons, in advanced PD and rodent models of severe dopamine depletion. Dendritic spine loss occurs via dysregulation of intraspine Cav1.3 L-type Ca(2+)channels and can be prevented, in animal models, by administration of the calcium channel antagonist, nimodipine. The impact of MSN dendritic spine loss in the parkinsonian striatum on dopamine neuron graft therapy remains unexamined. Using unilaterally parkinsonian Sprague-Dawley rats, we tested the hypothesis that MSN dendritic spine preservation through administration of nimodipine would result in improved therapeutic benefit and diminished graft-induced behavioral abnormalities in rats grafted with embryonic ventral midbrain cells. Analysis of rotational asymmetry and spontaneous forelimb use in the cylinder task found no significant effect of dendritic spine preservation in grafted rats. However, analyses of vibrissae-induced forelimb use, levodopa-induced dyskinesias and graft-induced dyskinesias showed significant improvement in rats with dopamine grafts associated with preserved striatal dendritic spine density. Nimodipine treatment in this model did not impact dopamine graft survival but allowed for increased graft reinnervation of striatum. Taken together, these results demonstrate that even with grafting suboptimal numbers of cells, maintaining normal spine density on target MSNs results in overall superior behavioral efficacy of dopamine grafts. PMID:20105237

Soderstrom, Katherine E; O'Malley, Jennifer A; Levine, Nathan D; Sortwell, Caryl E; Collier, Timothy J; Steece-Collier, Kathy

2010-01-25

330

Type 2 Innate Immunity in Helminth Infection Is Induced Redundantly and Acts Autonomously following CD11c+ Cell Depletion  

PubMed Central

Infection with gastrointestinal helminths generates a dominant type 2 response among both adaptive (Th2) and innate (macrophage, eosinophil, and innate lymphoid) immune cell types. Two additional innate cell types, CD11chigh dendritic cells (DCs) and basophils, have been implicated in the genesis of type 2 immunity. Investigating the type 2 response to intestinal nematode parasites, including Heligmosomoides polygyrus and Nippostrongylus brasiliensis, we first confirmed the requirement for DCs in stimulating Th2 adaptive immunity against these helminths through depletion of CD11chigh cells by administration of diphtheria toxin to CD11c.DOG mice. In contrast, responsiveness was intact in mice depleted of basophils by antibody treatment. Th2 responses can be induced by adoptive transfer of DCs, but not basophils, exposed to soluble excretory-secretory products from these helminths. However, innate type 2 responses arose equally strongly in the presence or absence of CD11chigh cells or basophils; thus, in CD11c.DOG mice, the alternative activation of macrophages, as measured by expression of arginase-1, RELM-?, and Ym-1 (Chi3L3) in the intestine following H. polygyrus infection or in the lung following N. brasiliensis infection, was unaltered by depletion of CD11c-expressing DCs and alveolar macrophages or by antibody-mediated basophil depletion. Similarly, goblet cell-associated RELM-? in lung and intestinal tissues, lung eosinophilia, and expansion of innate lymphoid (“nuocyte”) populations all proceeded irrespective of depletion of CD11chigh cells or basophils. Thus, while CD11chigh DCs initiate helminth-specific adaptive immunity, innate type 2 cells are able to mount an autonomous response to the challenge of parasite infection.

Smith, Katherine A.; Harcus, Yvonne; Garbi, Natalio; Hammerling, Gunter J; MacDonald, Andrew S.

2012-01-01

331

Type 2 innate immunity in helminth infection is induced redundantly and acts autonomously following CD11c(+) cell depletion.  

PubMed

Infection with gastrointestinal helminths generates a dominant type 2 response among both adaptive (Th2) and innate (macrophage, eosinophil, and innate lymphoid) immune cell types. Two additional innate cell types, CD11c(high) dendritic cells (DCs) and basophils, have been implicated in the genesis of type 2 immunity. Investigating the type 2 response to intestinal nematode parasites, including Heligmosomoides polygyrus and Nippostrongylus brasiliensis, we first confirmed the requirement for DCs in stimulating Th2 adaptive immunity against these helminths through depletion of CD11c(high) cells by administration of diphtheria toxin to CD11c.DOG mice. In contrast, responsiveness was intact in mice depleted of basophils by antibody treatment. Th2 responses can be induced by adoptive transfer of DCs, but not basophils, exposed to soluble excretory-secretory products from these helminths. However, innate type 2 responses arose equally strongly in the presence or absence of CD11c(high) cells or basophils; thus, in CD11c.DOG mice, the alternative activation of macrophages, as measured by expression of arginase-1, RELM-?, and Ym-1 (Chi3L3) in the intestine following H. polygyrus infection or in the lung following N. brasiliensis infection, was unaltered by depletion of CD11c-expressing DCs and alveolar macrophages or by antibody-mediated basophil depletion. Similarly, goblet cell-associated RELM-? in lung and intestinal tissues, lung eosinophilia, and expansion of innate lymphoid ("nuocyte") populations all proceeded irrespective of depletion of CD11c(high) cells or basophils. Thus, while CD11c(high) DCs initiate helminth-specific adaptive immunity, innate type 2 cells are able to mount an autonomous response to the challenge of parasite infection. PMID:22851746

Smith, Katherine A; Harcus, Yvonne; Garbi, Natalio; Hämmerling, Günter J; MacDonald, Andrew S; Maizels, Rick M

2012-07-30

332

Effects of DFMO-induced polyamine depletion on human tumor cell sensitivity to antineoplastic DNA-crosslinking drugs.  

PubMed

We investigated the effect of pretreatment with difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, on the cytocidal responses of four human adenocarcinoma cell lines to two alkylating and crosslinking agents: chlorambucil and N,N',N"-triethylenethiophosphoramide (thiotepa). The cell lines studied included HuTu-80 (duodenum), HT-29 (colon), ME-180 (cervix), and A-427 (lung). A 48- to 72-h pretreatment with DFMO reduced intracellular putrescine and spermidine contents to less than 10% and less than 1% of control levels. This treatment also caused a 30%-70% decline in spermine content. Survival of control and DFMO-pretreated cells after treatment with chlorambucil or thiotepa was measured by a plating efficiency assay. For three of the four lines studied, the DFMO-induced partial polyamine depletion significantly protected cells from the lethal effects of chlorambucil. In ME-180 cultures alone, DFMO pretreatment did not alter the cytocidal efficacy of chlorambucil. Addition of exogenous putrescine to cultures of HuTu-80, HT-29, or A-427 24 h after DFMO addition but 24 h before treatment with chlorambucil reversed the polyamine depletion and its protective effects on chlorambucil-induced cell kill. In contrast to the above observations, DFMO and partial polyamine depletion had no effect on cell survival after thiotepa treatment for any of the cell lines investigated. PMID:3084110

Seidenfeld, J; Komar, K A; Naujokas, M F; Block, A L

1986-01-01

333

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

334

The cystine-glutamate transporter enhancer N-acetyl-L-cysteine attenuates cocaine-induced changes in striatal dopamine but not self-administration in squirrel monkeys.  

PubMed

Extrasynaptic glutamate has been shown to regulate dopamine function in the mesocorticolimbic pathway, which plays an important role in the behavioral pharmacology of psychostimulants. Basal levels of glutamate are primarily regulated by the cystine-glutamate transporter and provide glutamatergic tone on extrasynaptic glutamate receptors. The present study examined the effects of a cystine-glutamate transporter enhancer on the neurochemical and behavioral effects of cocaine and amphetamine in nonhuman primates. It was hypothesized that augmenting extrasynaptic glutamate release with N-acetyl-L-cysteine (NAC), a cystine prodrug, would attenuate cocaine- or amphetamine-induced increases in extracellular dopamine and their corresponding behavioral-stimulant and reinforcing effects. In vivo microdialysis was used to evaluate cocaine-induced changes in extracellular dopamine (DA) in the caudate nucleus (n=3). NAC significantly attenuated cocaine-induced increases in dopamine but had inconsistent effects on amphetamine-induced increases in dopamine (n=4). Separate groups of subjects were either trained on a fixed-interval schedule of stimulus termination (n=6) or on a second-order schedule of self-administration (n=5) to characterize the behavioral-stimulant and reinforcing effects of psychostimulants, respectively. Systemic administration of NAC did not alter the behavioral-stimulant effects of either cocaine or amphetamine. Furthermore, cocaine self-administration and reinstatement of previously extinguished cocaine self-administration were not altered by pretreatment with NAC. Hence, drug interactions on caudate neurochemistry in vivo were not reflected in behavioral measures in squirrel monkeys. The present results in nonhuman primates do not support the use of NAC as a pharmacotherapy for cocaine abuse, although rodent and clinical studies suggest otherwise. PMID:22244740

Bauzo, Rayna M; Kimmel, Heather L; Howell, Leonard L

2011-12-31

335

Effect of acute and chronic olanzapine treatment on phencyclidine-induced behavioral sensitization in rats with neonatal dopamine loss.  

PubMed

In agreement with previous work, adult rats given selective lesions to dopamine (DA)-containing neurons as neonates exhibited a greater behavioral sensitization to repeated phencyclidine (PCP) treatment in comparison to sham-lesioned controls. Acute administration of olanzapine (1-5 mg/kg ip) or clozapine (15 mg/kg ip) decreased sensitized PCP-induced activity in both lesioned and control animals. Acute haloperidol (0.5 mg/kg ip) had no impact on PCP responsiveness in lesioned animals, but significantly antagonized PCP effects in sham-lesioned controls. Ketanserin, a selective 5-HT(2A)/5-HT(2C)-receptor antagonist, significantly reduced PCP activation in both lesioned and control rats, suggesting that the efficacy of atypical antipsychotics against PCP-induced sensitized responses may be mediated by one of the 5-HT(2)-receptor subtypes. A 6-week chronic regimen of orally administered olanzapine, clozapine, or haloperidol failed to block the sensitization induced by repeated PCP exposure. However, a 10-month oral olanzapine treatment significantly blunted the behavioral sensitization to repeated PCP exposure in lesioned animals, even after withdrawal from chronic olanzapine for more than 3 weeks. A 10-month oral haloperidol treatment had no effect on the sensitization induced by repeated PCP dosing. The persistent effect of chronic olanzapine administration on PCP sensitization may be relevant to the chronic therapeutic efficacy of atypical antipsychotics treating schizophrenia-a clinical syndrome linked to enhanced sensitivity to N-methyl-d-aspartate (NMDA)-receptor antagonists. PMID:15159133

Moy, Sheryl S; Fernandes, Alda; Qian, Ying; Rotella, Dana J; Kostrewa, Richard M; Breese, George R

2004-05-01

336

Effects of dopamine D2 receptor (DRD2) and transporter (SLC6A3) polymorphisms on smoking cue-induced cigarette craving among African-American smokers  

Microsoft Academic Search

Cue-induced craving for addictive substances has long been known to contribute to the problem of persistent addiction in humans. Research in animals over the past decade has solidly established the central role of dopamine in cue-induced craving for addictive substances, including nicotine. Analogous studies in humans, however, are lacking, especially among African-American smokers, who have lower quit rates than Caucasian

J Erblich; C Lerman; D W Self; G A Diaz; D H Bovbjerg; Erblich

2005-01-01

337

Scopolamine augments C- fos and zif\\/268 messenger rna expression induced by the full D 1 dopamine receptor agonist SKF-82958 in the intact rat striatum  

Microsoft Academic Search

It is generally accepted that the widely used, partial dopamine D1 receptor agonist, SKF-38393, does not induce immediate early gene expression in striatal projection neurons unless D1 receptors are sensitized and uncoupled from D2 receptors by 6-hydroxydopamine lesions or reserpine treatment. In contrast, this study demonstrates, using quantitative in situ hybridization, that the full D1 receptor agonist, SKF-82958, induced robust

J. Q. Wang; J. F. McGinty

1996-01-01

338

Wnt\\/?-catenin pathway activation and myogenic differentiation are induced by cholesterol depletion  

Microsoft Academic Search

Myogenic differentiation is a multistep process that begins with the commitment of mononucleated precursors that withdraw from cell cycle. These myoblasts elongate while aligning to each other, guided by the recognition between their membranes. This step is followed by cell fusion and the formation of long and striated multinucleated myotubes. We have recently shown that cholesterol depletion by methyl-?-cyclodextrin (M?CD)

Cláudia S. Mermelstein; Débora M. Portilho; Fábio A. Mendes; Manoel L. Costa; José Garcia Abreu

2007-01-01

339

Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion  

Microsoft Academic Search

Zidovudine is known to be responsible for a mitochondrial myopathy with ragged-red fibres and mitochondrial DNA depletion in muscle. Lactic acidosis alone or associated with hepatic abnormalities has also been reported. A single report mentioned the concomitant occurrence of muscular and hepatic disturbances and lactic acidosis in a patient receiving zidovudine, but muscle and liver tissues were not studied. A

Patrick Chariot; Irène Drogou; Isabelle de Lacroix-Szmania; Marie-Christine Eliezer-Vanerot; Bénédicte Chazaud; Anne Lombès; Annette Schaeffer; Elie Serge Zafrani

1999-01-01

340

Novel Pharmacological Approaches for Treatment of Neurotoxicity Induced by Chronic Exposure to Depleted Uranium.  

National Technical Information Service (NTIS)

The chemical properties and high density of depleted uranium (DU) render the metal well suited for military purposes. The U. S. Army utilizes DU for tank armor and in munitions, deployed such weapons in the first Gulf War, and is currently deploying them ...

S. D. Lasley

2011-01-01

341

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

Microsoft Academic Search

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

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

1991-01-01

342

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

2009-12-02

343

Glutathione depletion by DL-buthionine-SR-sulfoximine (BSO) potentiates X-ray-induced chromosome lesions after liquid holding recovery  

SciTech Connect

The impact of intracellular glutathione depletion on chromosome damage induced by X irradiation under aerobic conditions was investigated in two different cell lines, Ehrlich ascites tumor cells (EATC) and Chinese hamster ovary cells (CHO-K1). Thiol-depleted cell cultures in plateau phase were obtained by prolonged incubation in growth medium containing DL-buthionine-SR-sulfoximine (BSO), a specific inhibitor of gamma-glutamyl-cysteine synthetase. Cells were then assayed using the procedures of G. L. Ellmann and J. Sedlack and R.H. Lindsay for non-protein bound SH (NPSH), glutathione (GSH), and total SH (TSH). In both cell lines GSH was reduced to less than 10% of controls at higher BSO concentrations around 1 mM, whereas TSH and NPSH were affected to only 40-60%. In EATC pretreated with up to 1 mM BSO for 72 h, increased levels of spontaneously occurring micronuclei were found. At BSO concentrations above 200 microM, both cell lines showed a potentiation of chromosome lesions scored as micronuclei and induced under aerobic X irradiation when liquid holding recovery in the original nutrient-depleted medium was performed; the extent of chromosome damage eventually reached that which could be obtained by application of beta-arabinofuranosyladenine (beta-araA), known to inhibit DNA repair processes by blocking DNA polymerases. It is therefore suggested that GSH depletion causes impairment of repair of lesions leading to chromosome deletions and subsequently to micronuclei. In contrast to CHO cell cultures, EATC showed a reversion of the potentiation effect as indicated by a decrease in the micronucleus content during prolonged incubation in the presence of BSO in the millimolar range.

Bertsche, U.; Schorn, H.

1986-03-01

344

Subchronic Caffeine Exposure Induces Sensitization to Caffeine and Cross-Sensitization to Amphetamine Ipsilateral Turning Behavior Independent from Dopamine Release  

Microsoft Academic Search

We have recently shown that repeated exposure to caffeine sensitizes rats to the motor activating effects of dopamine D1 and D2 receptor agonists. In order to study the role of dopamine in this effect, sensitization to caffeine and cross-sensitization between caffeine and amphetamine was evaluated by studying turning behavior and in vivo striatal dopamine release in unilaterally 6-hydroxydopamine-lesioned rats. Administration

Omar Cauli; Annalisa Pinna; Valentina Valentini; Micaela Morelli

2003-01-01

345

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

PubMed Central

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

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

2011-01-01

346

Amisulpride-induced acute akathisia in OCD: an example of dysfunctional dopamine-serotonin interactions?  

PubMed Central

We report about a clinical observation in a well-characterized group of patients with obsessive–compulsive disorder (OCD) during an experimental medicine study in which a single dose of amisulpride (a selective D2/3 antagonist) was administered. Almost half of the OCD patients, in particular those with less severe obsessive–compulsive symptoms, experienced acute akathisia in response to the amisulpride challenge. This unexpectedly high incidence of akathisia in the selective serotonin reuptake inhibitor (SSRI)-treated patients with OCD suggests that individual differences in dopamine–serotonin interactions underlie the clinical heterogeneity of OCD, and may thus explain the insufficiency of SSRI monotherapy in those patients not experiencing a satisfactory outcome in symptom reduction. We further speculate about the neuropathology possibly underlying this clinical observation and outline a testable hypothesis for future molecular imaging studies.

Ersche, Karen D; Cumming, Paul; Craig, Kevin J; Muller, Ulrich; Fineberg, Naomi A; Bullmore, Edward T; Robbins, Trevor W

2013-01-01

347

Amisulpride-induced acute akathisia in OCD: an example of dysfunctional dopamine-serotonin interactions?  

PubMed

We report about a clinical observation in a well-characterized group of patients with obsessive-compulsive disorder (OCD) during an experimental medicine study in which a single dose of amisulpride (a selective D?/? antagonist) was administered. Almost half of the OCD patients, in particular those with less severe obsessive-compulsive symptoms, experienced acute akathisia in response to the amisulpride challenge. This unexpectedly high incidence of akathisia in the selective serotonin reuptake inhibitor (SSRI)-treated patients with OCD suggests that individual differences in dopamine-serotonin interactions underlie the clinical heterogeneity of OCD, and may thus explain the insufficiency of SSRI monotherapy in those patients not experiencing a satisfactory outcome in symptom reduction. We further speculate about the neuropathology possibly underlying this clinical observation and outline a testable hypothesis for future molecular imaging studies. PMID:21746752

Ersche, Karen D; Cumming, Paul; Craig, Kevin J; Müller, Ulrich; Fineberg, Naomi A; Bullmore, Edward T; Robbins, Trevor W

2011-07-11

348

Comparison of the MK-801-induced increase in non-rewarded appetitive responding with dopamine agonists and locomotor activity in rats.  

PubMed

Systemic administration of the noncompetitive N-methyl-D-aspartate (NMDA)- receptor antagonist, MK-801, has been proposed to model cognitive deficits similar to those seen in patients with schizophrenia. Evidence has shown that MK-801 increases the probability of operant responding during extinction, possibly modeling perseveration, as would be seen in patients with schizophrenia. This MK-801-induced behavioral perseveration is reversed by dopamine receptor antagonism. To further explore the role of dopamine in this behavioral change, the current study sought to determine if the MK-801-induced increase in non-rewarded operant responding could be mimicked by dopamine agonism and determine how it was related to locomotor activity. Male Long Evans rats were treated systemically with MK-801, cocaine, GBR12909 or apomorphine (APO) and given a single trial operant extinction session, followed by a separate assessment of locomotor activity. Both MK-801 (0.05 mg/kg) and cocaine (10 mg/kg) significantly increased responding during the extinction session and both increased horizontal locomotor activity. No dose of GBR-12909 (5, 10 or 20 mg/kg) was found to effect non-rewarded operant responding or locomotor activity. APO (0.05, 0.5, 2 or 5 mg/kg) treatment produced a dose-dependent decrease in both operant responding and locomotor activity. These results suggest the possibility that, rather than a primary influence of increased dopamine concentration on elevating bar-pressing responses during extinction, other neurotransmitter systems may be involved. PMID:23761388

Davis-Macnevin, Parnell L; Dekraker, Jordan; Ladouceur, Liane; Holahan, Matthew R

2013-06-12

349

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

PubMed Central

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

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

1995-01-01

350

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

351

Cocaine-Induced Behavioral Sensitization in Mice: Effects of Microinjection of Dopamine D2 Receptor Antagonist into the Nucleus Accumbens  

PubMed Central

To determine the role of dopamine D2 receptor (D2R) in the nucleus accumbens (NAc) core in cocaine-induced behavioral sensitization, D2R antagonist, raclopride was bilaterally microinjected (2.5 or 5 nmol) into the NAc core of WT and D2R-/- mice and the initiation and expression phase of cocaine-mediated locomotor sensitization were analyzed. WT and D2R knockout (D2R-/-) mice received bilateral injections of either saline, or raclopride at the NAc core 30 min before each of five daily repeated injections of saline or cocaine (15 mg/kg i.p.). Following 2 weeks of withdrawal after repeated exposure to cocaine, the animals were pre-treated with an intra-accumbal injection of vehicle or raclopride before receiving a systemic cocaine challenge for the expression of sensitization. Animals which had been microinjected raclopride into NAc core displayed the enhancement of cocaine-induced behavioral response for the initiation but also for the expression of sensitization in WT as well as in D2R-/- mice, which was thus unaltered as compared to vehicle-injected control group. These results suggest that D2R in NAc core is not involved in cocaine-induced behavioral sensitization.

Jung, Eun-Sol; Lee, Hyo Jin; Sim, Hye-Ri

2013-01-01

352

Anterior hypothalamic dopamine D2 receptors modulate adolescent anabolic/androgenic steroid-induced offensive aggression in the Syrian hamster.  

PubMed

In the Syrian hamster, treatment with anabolic/androgenic steroids (AAS) throughout adolescence increases dopamine and D2 receptor expression in the anterior hypothalamus (AH), a brain region implicated in the control of aggression. D2 receptor antagonists have reduced aggression in various species and animal models. However, these studies used systemic administration of drugs and reported concomitant changes in mobility. These data complicate the question of whether pharmacology targeting D2 receptors is specific to aggression or whether these drugs exert their antiaggressive effects through nonspecific mechanisms. To resolve this discrepancy, the current studies investigate whether administration of the D2 receptor antagonist eticlopride (0.01-10.0 microg in a final volume of 0.5 microl) into the AH modulates AAS-induced aggression. Antagonism of AH D2 receptors effectively suppressed AAS-induced aggression beginning at the 0.1 microg dose, with higher doses producing a floor effect, when compared with AAS-treated animals injected with saline into the AH. Importantly, these reductions in aggressive responding occurred in the absence of changes in locomotor behavior. Our findings identify a neuroanatomical locus where D2 receptor antagonism suppresses adolescent AAS-induced aggression in the absence of alterations to general mobility. PMID:20555255

Schwartzer, Jared J; Melloni, Richard H

2010-07-01

353

PTEN deletion enhances survival, neurite outgrowth and function of dopamine neuron grafts to MitoPark mice  

PubMed Central

Clinical trials in Parkinson’s disease have shown that transplants of embryonic mesencephalic dopamine neurons form new functional connections within the host striatum, but the therapeutic benefits have been highly variable. One obstacle has been poor survival and integration of grafted dopamine neurons. Activation of Akt, a serine/threonine kinase that promotes cell survival and growth, increases the ability of neurons to survive after injury and to regenerate lost neuronal connections. Because the lipid phosphatase, phosphatase and tensin homolog (PTEN) inhibits Akt, we generated a mouse with conditional knock-out of PTEN in dopamine neurons, leading to constitutive expression of Akt in these neurons. Ventral mesencephalic tissue from dopamine phosphatase and tensin homologue knock-out or control animals was then transplanted bilaterally into the dopamine depleted striata of MitoPark mice that express a parkinsonian phenotype because of severe respiratory chain dysfunction in dopamine neurons. After transplantation into MitoPark mice, PTEN-deficient dopamine neurons were less susceptible to cell death, and exhibited a more extensive pattern of fibre outgrowth compared to control grafts. Voltammetric measurements demonstrated that dopamine release and reuptake were significantly increased in the striata of animals receiving dopamine PTEN knock-out transplants. These animals also displayed enhanced spontaneous and drug-induced locomotor activity, relative to control transplanted MitoPark mice. Our results suggest that disinhibition of the Akt-signalling pathway may provide a valuable strategy to enhance survival, function and integration of grafted dopamine neurons within the host striatum and, more generally, to improve survival and integration of different forms of neural grafts.

Zhang, YaJun; Granholm, Ann-Charlotte; Huh, Kyounghee; Shan, Lufei; Diaz-Ruiz, Oscar; Malik, Nasir; Olson, Lars; Hoffer, Barry J.; Lupica, Carl R.; Hoffman, Alexander F.

2012-01-01

354

PTEN deletion enhances survival, neurite outgrowth and function of dopamine neuron grafts to MitoPark mice.  

PubMed

Clinical trials in Parkinson's disease have shown that transplants of embryonic mesencephalic dopamine neurons form new functional connections within the host striatum, but the therapeutic benefits have been highly variable. One obstacle has been poor survival and integration of grafted dopamine neurons. Activation of Akt, a serine/threonine kinase that promotes cell survival and growth, increases the ability of neurons to survive after injury and to regenerate lost neuronal connections. Because the lipid phosphatase, phosphatase and tensin homolog (PTEN) inhibits Akt, we generated a mouse with conditional knock-out of PTEN in dopamine neurons, leading to constitutive expression of Akt in these neurons. Ventral mesencephalic tissue from dopamine phosphatase and tensin homologue knock-out or control animals was then transplanted bilaterally into the dopamine depleted striata of MitoPark mice that express a parkinsonian phenotype because of severe respiratory chain dysfunction in dopamine neurons. After transplantation into MitoPark mice, PTEN-deficient dopamine neurons were less susceptible to cell death, and exhibited a more extensive pattern of fibre outgrowth compared to control grafts. Voltammetric measurements demonstrated that dopamine release and reuptake were significantly increased in the striata of animals receiving dopamine PTEN knock-out transplants. These animals also displayed enhanced spontaneous and drug-induced locomotor activity, relative to control transplanted MitoPark mice. Our results suggest that disinhibition of the Akt-signalling pathway may provide a valuable strategy to enhance survival, function and integration of grafted dopamine neurons within the host striatum and, more generally, to improve survival and integration of different forms of neural grafts. PMID:22961549

Zhang, YaJun; Granholm, Ann-Charlotte; Huh, Kyounghee; Shan, Lufei; Diaz-Ruiz, Oscar; Malik, Nasir; Olson, Lars; Hoffer, Barry J; Lupica, Carl R; Hoffman, Alexander F; Bäckman, Cristina M

2012-09-01

355

Studies on the role of dopamine and dopamine blockers in gastroduodenal motility.  

PubMed

In vitro studies on an intact gastroduodenal preparation of the guinea-pig indicated that dopamine inhibited motor activity via a direct action on the gastrointestinal wall. Dopamine-induced relaxations were prevented by dopamine antagonists, which also exerted intrinsic stimulatory effects and improved gastroduodenal coordination. These effects were confirmed in vivo on conscious dogs. The results cannot be explained by an interaction with alpha- receptors, since alpha-adrenergic blocking concentrations of prazosin were inactive against dopamine, and dopamine-blocking concentrations of domperidone did not interfere with noradrenaline-induced relaxations. Pharmacological evidence confirmed the presence of dopamine receptors in the stomach of conscious dogs. The presence of specific dopamine receptors in the gastrointestinal tract is strongly indicated, and an important role for endogenous dopamine as an inhibitory neuromodulator of gastroduodenal motility is suggested. PMID:6382581

Van Nueten, J M; Schuurkes, J A

1984-01-01

356

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

Microsoft Academic Search

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

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

1991-01-01

357

Toll-Like Receptors 2 and 4 Contribute to Sepsis-Induced Depletion of Spleen Dendritic Cells?  

PubMed Central

Depletion of dendritic cells (DC) in secondary lymphoid organs is a hallmark of sepsis-induced immune dysfunction. In this setting, we investigated if Toll-like receptor (TLR)-dependent signaling might modulate the maturation process and the survival of DC. Using a model of sublethal polymicrobial sepsis induced by cecal ligation and puncture, we investigated the quantitative and functional features of spleen DC in wild-type, TLR2?/?, TLR4?/?, and TLR2?/? TLR4?/? mice. By 24 h, a decrease in the relative percentage of CD11chigh spleen DC occurred in wild-type mice but was prevented in TLR2?/?, TLR4?/?, and TLR2?/? TLR4?/? mice. In wild-type mice, sepsis dramatically affected both CD11c+ CD8?+ and CD11c+ CD8?? subsets. In all three types of knockout mice studied, the CD11c+ CD8?+ subset followed a depletion pattern similar to that for wild-type mice. In contrast, the loss of CD11c+ CD8?? cells was attenuated in TLR2?/? and TLR4?/? mice and completely prevented in TLR2?/? TLR4?/? mice. Accordingly, apoptosis of spleen DC was increased in septic wild-type mice and inhibited in knockout mice. In addition we characterized the functional features of spleen DC obtained from septic mice. As shown by increased expression of major histocompatibility complex class II and CD86, polymicrobial sepsis induced maturation of DC, with subsequent increased capacity to prime T lymphocytes, similarly in wild-type and knockout mice. In response to CpG DNA stimulation, production of interleukin-12 was equally impaired in DC obtained from wild-type and knockout septic mice. In conclusion, although dispensable for the DC maturation process, TLR2 and TLR4 are involved in the mechanisms leading to depletion of spleen DC following polymicrobial sepsis.

Pene, Frederic; Courtine, Emilie; Ouaaz, Fatah; Zuber, Benjamin; Sauneuf, Bertrand; Sirgo, Gonzalo; Rousseau, Christophe; Toubiana, Julie; Balloy, Viviane; Chignard, Michel; Mira, Jean-Paul; Chiche, Jean-Daniel

2009-01-01

358

Functional potencies of dopamine agonists and antagonists at human dopamine D 2 and D 3 receptors  

Microsoft Academic Search

We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D2 and D3 receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D2L and D2S receptors (hD2L-Low,

Yoshihiro Tadori; Robert A. Forbes; Robert D. McQuade; Tetsuro Kikuchi

2011-01-01

359

Effects of a dopamine D1 agonist on ketamine-induced spatial working memory dysfunction in common marmosets.  

PubMed

It is considered that functional deficiency of the NMDA receptors in the prefrontal cortex (PFC) is one of the causes of the cognitive impairment observed in schizophrenia. As non-human primates display more developed PFC than rodents, they are considered to be useful experimental animals for improving the predictive validity of models used to discover new drugs for treating cognitive dysfunction. The aim of this study was to develop a convenient model of the cognitive impairment observed in schizophrenia using common marmosets and the CANTAB system and to test whether a full agonist of the dopamine D1 receptor (SKF-81297) was effective against the cognitive impairment induced in this model. We administered the NMDA receptor antagonist ketamine (1.5-16mg/kg, i.m.) to the marmosets to induce cognitive impairment and then evaluated their working memory function using the CANTAB spatial working memory (SWM) test. The marmosets' working memory was impaired by subanesthetic doses of ketamine. Next, we tested the effect of SKF-81297 (3 or 10mg/kg, p.o.) on this ketamine-induced cognitive dysfunction. The marmosets were administered SKF-81297 30min before the ketamine injection. Pretreatment with SKF-81297 reversed the ketamine-induced cognitive deficiency. In this study, we found that a D1 receptor agonist, which has been reported to enhance cognitive function, reversed ketamine-induced cognitive impairment in marmosets, which suggests that our marmoset model could be a useful tool for predicting the clinical efficacy of cognitive-enhancing drugs. PMID:23608483

Nakako, Tomokazu; Murai, Takeshi; Ikejiri, Masaru; Ishiyama, Takeo; Taiji, Mutsuo; Ikeda, Kazuhito

2013-04-19

360

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 naïve 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

2012-06-18

361

Solubilization and characterization of D2-dopamine receptors in an estrone-induced, prolactin-secreting rat pituitary adenoma.  

PubMed

D2-dopamine (3,4-dihydroxyphenylethylamine) receptors were successfully solubilized with 3-[(3-cholamidopropyl)-dimethylammonio]-1-propane sulfonate from an estrone-induced rat pituitary adenoma. Forty-five percent of initial protein and 48% of initial [3H]spiroperidol binding sites were solubilized. The high affinity as well as the stereoselectivity of the sites was preserved. The order of potency of dopaminergic agonists was found to be typical of D2 receptors. Target size analysis by radiation inactivation indicated a molecular weight of 143,000 +/- 3,000 and of 106,000 +/- 4,000 daltons for membrane-bound and solubilized receptors, respectively. This suggests the loss of a 37,000-dalton subunit during solubilization without significant modification of binding characteristics. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of receptor protein preparation photolabeled with N-(p-azido-m[125I]iodophenethyl)spiroperidol confirmed the existence of a 94,000-dalton peptide which probably constitutes the ligand binding site of the receptor. Thus, our data indicate that chronic estrogen treatment of rats, although inducing a pituitary adenoma, does not modify the pharmacological characteristics of D2 receptors. These data suggest therefore that these adenoma may represent an ideal source of material for further biochemical characterization of D2 receptors. PMID:3760878

Bouvier, C; Potier, M; Beauregard, G; Lafond, J; Amlaiky, N; Caron, M G; Collu, R

1986-11-01

362

Novel receptor site involved in enhancement of stimulus-induced acetylcholine, dopamine, and serotonin release  

SciTech Connect

The cognitive enhancer DuP 996 (3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one) and its structural analogs enhance the K(+)-stimulated release of acetylcholine, dopamine, and serotonin in brain slices, without effect on basal release. A novel receptor site labeled by (3H)DuP 996 has been identified. The (3H)DuP 996 binding site has a Kd of 19 nM and a Bmax of 102 fmol/mg of protein. Binding to this site is specific, saturable, reversible, and time, pH, and temperature dependent. Specific binding is decreased by treatment with trypsin and not affected by phospholipase C. Specific binding is inhibited by Ca2+ and increased by Mn2+ but not affected by Na+, K+, or Mg2+. The (3H)DuP 996 binding sites are heterogeneously distributed in brain, with striatum and hypothalamus having highest density and cerebellum lowest. The (3H)DuP 996 binding site does not belong to any known class of receptor site, because (3H)DuP 996 binding could not be displaced by a broad variety of standard pharmacological agents and neuropeptides. Physiological significance of this binding site is suggested by the excellent correlation between the binding affinity for this site and the potency to enhance K(+)-stimulated release of acetylcholine for a series of DuP 996 analogs. Ligands for this receptor site may have therapeutic potential for the treatment of cognitive deficits and neurodegenerative diseases.

Tam, S.W.; Rominger, D.; Nickolson, V.J. (Central Nervous System Diseases Research, Du Pont Merck Pharmaceutical Company, Wilmington, DE (USA))

1991-07-01

363

Immunotherapy of Murine Retrovirus-Induced Acquired Immunodeficiency by CD4 T Regulatory Cell Depletion and PD-1 Blockade ?  

PubMed Central

LP-BM5 retrovirus induces a complex disease featuring an acquired immunodeficiency syndrome termed murine AIDS (MAIDS) in susceptible strains of mice, such as C57BL/6 (B6). CD4 T helper effector cells are required for MAIDS induction and progression of viral pathogenesis. CD8 T cells are not needed for viral pathogenesis, but rather, are essential for protection from disease in resistant strains, such as BALB/c. We have discovered an immunodominant cytolytic T lymphocyte (CTL) epitope encoded in a previously unrecognized LP-BM5 retroviral alternative (+1 nucleotide [nt]) gag translational open reading frame. CTLs specific for this cryptic gag epitope are the basis of protection from LP-BM5-induced immunodeficiency in BALB/c mice, and the inability of B6 mice to mount an anti-gag CTL response appears critical to the initiation and progression of LP-BM5-induced MAIDS. However, uninfected B6 mice primed by LP-BM5-induced tumors can generate CTL responses to an LP-BM5 retrovirus infection-associated epitope(s) that is especially prevalent on such MAIDS tumor cells, indicating the potential to mount a protective CD8 T-cell response. Here, we utilized this LP-BM5 retrovirus-induced disease system to test whether modulation of normal immune down-regulatory mechanisms can alter retroviral pathogenesis. Thus, following in vivo depletion of CD4 T regulatory (Treg) cells and/or selective interruption of PD-1 negative signaling in the CD8 T-cell compartment, retroviral pathogenesis was significantly decreased, with the combined treatment of CD4 Treg cell depletion and PD-1 blockade working in a synergistic fashion to substantially reduce the induction of MAIDS.

Li, Wen; Green, William R.

2011-01-01

364

Cysteamine can induce duodenal ulceration in rats without depletion of immunoreactive somatostatin.  

PubMed

Single subcutaneous administration of cysteamine (2-aminoethanethiol, CSH) produces duodenal ulceration in rats within 24 h. Depletion of circulating and tissue somatostatin (SOM), hypergastrinemia and gastric acid hypersecretion have all been postulated as the pathophysiological response to CSH leading to ulceration. The purpose of this study was to analyze the synthesis, storage and secretion of gastrin and SOM as well as structural changes in SOM peptide after CSH treatment. Injection of 300 mg/kg (s.c.) of CSH caused macroscopic duodenal ulcers in seven out of eight rats at 24 h. Hypergastrinemia was seen within 30 min (from 23 +/- 4 to 74 +/- 20 pmol/l), and persisted for 4 h. Antral gastrin content was elevated at 30 min (2539 +/- 114 pmol/g) when compared to saline controls (1589 +/- 101 pmol/g). Plasma SOM did not change over the 24 h but antral SOM increased at 30 min (from 120 +/- 3 to 230 +/- 23 pmol/g) and remained elevated at 2 h (374 +/- 48 pmol/g) and 4 h (357 +/- 37 pmol/g). Fundic and duodenal SOM followed a similar pattern. Antral SOM mRNA was also elevated over the first 4 h (3-fold increase, P less than 0.05). HPLC analysis of antral tissue extracts revealed the presence of additional molecular forms of SOM which, however, differed from the major products of in vitro reduction with either CSH or dithiothreitol. Thus, the in vivo effect of CSH on SOM cannot be solely explained by a reductive opening of the disulphide bond. These results suggest that duodenal ulceration in rats treated with CSH is not related in a simple fashion to depletion of immunoreactive SOM. Early induction of hypergastrinemia may be important in the onset of ulceration. The value of CSH as a SOM depleting tool in gastrointestinal tissue must remain in doubt. PMID:1687422

Kapuscinski, M; Shulkes, A; Green, M; Read, D; MacLellan, D G

1991-11-26

365

Differential modulation of ghrelin-induced GH and LH release by PACAP and dopamine in goldfish pituitary cells.  

PubMed

Ghrelin (GRLN) participates in multiple physiological processes, including the regulation of growth hormone (GH) and luteinizing hormone (LH) release. In the goldfish, neuroendocrine control of GH and LH release are multifactorial. In this system, pituitary adenylate cyclase-activating polypeptide (PACAP)-stimulated GH and LH secretion, as well as dopamine (DA)-induced GH release, are mediated by protein kinase A (PKA)-dependent, but protein kinase C (PKC)-independent, mechanisms. In addition, DA inhibits LH secretion by actions at sites along both PKA and PKC signaling pathways. Recently, goldfish GRLN (gGRLN19) has been shown to induce GH release via PKC, and LH secretion via both PKC and PKA. To further understand the neuroendocrine regulation of goldfish GH and LH release, we examined the effects of DA and PACAP on gGRLN19 actions in primary cultures of goldfish pituitary cells in perifusion and in Ca(2+)-imaging experiments. Consistent with their known intracellular signaling mechanisms in gonadotrophs, DA inhibited gGRLN19-induced LH release while cotreatment of PACAP and gGRLN19 did not produce additive LH responses. When applied prior to gGRLN19, PACAP potentiated gGRLN19-induced GH release and Ca(2+) signals within somatotrophs. In contrast, neither prior treatment with DA followed by gGRLN19 nor pretreatment with gGRLN19 prior to PACAP produced an enhanced GH release response. These observations suggest that PKA activators positively modulate gGRLN19 actions on goldfish somatotrophs in a ligand- and treatment order-specific manner. Results add to our understanding of the complexity of neuroendocrine control of GH and LH release at the pituitary cell level, and our understanding of GRLN action. PMID:23851105

Grey, Caleb L; Chang, John P

2013-07-09

366

Endogenous semicarbazide-sensitive amine oxidase (SSAO) inhibitor increases 1-methyl-4-phenylpyridinium ion (MPP +)-induced dopamine efflux by immobilization stress in rat striatum  

Microsoft Academic Search

The present study examined whether or not immobilization stress (IMMO)-inducible semicarbazide-sensitive amine oxidase (SSAO) inhibitor by separated gel filtration from 105,000g supernate in rat brain cytosol contribute to the dopamine (DA) efflux by 1-methyl-4-phenylpyridinium ion (MPP+) in the rat striatum. The isoelectric point (pI) value of this inhibitor was determined by isoelectric focusing (IEF)-gel electrophoresis to about 3.8. The application

Toshio Obata

2006-01-01

367

Decreased striatal dopamine transporter binding assessed with [ 123 I] FP-CIT in first-episode schizophrenic patients with and without short-term antipsychotic-induced parkinsonism  

Microsoft Academic Search

Rationale  Drug-induced parkinsonism (DIP) is one of the main causes of treatment drop-out in schizophrenic patients causing a high incidence\\u000a of relapse that leads patients to a bad clinical prognosis. The dopaminergic nigrostriatal pathway is involved in the movement\\u000a control, so the study of the dopamine transporter (DAT) could be of great value to determine its implication in the appearance\\u000a of

Jose J. Mateos; Francisco Lomeña; Eduardo Parellada; Emili Fernandez; Javier Pavia; Alberto Prats; Francisca Pons; Miquel Bernardo

2005-01-01

368

Dopamine D3 Receptor Ligands Block Nicotine-Induced Conditioned Place Preferences through a Mechanism that does not Involve Discriminative-Stimulus or Antidepressant-Like Effects  

Microsoft Academic Search

Environmental stimuli previously paired with drug taking appear to play a critical role in nicotine dependence. Converging anatomical, pharmacological, and behavioral evidence implicates dopamine D3 receptors (D3Rs) in the mechanisms underlying stimulus-controlled drug-seeking behavior. This study assessed the effects of BP 897, a D3R partial agonist and ST 198, a D3R antagonist, on nicotine-induced conditioned place preferences (CPPs), used as

Bernard Le Foll; Pierre Sokoloff; Holger Stark; Steven R Goldberg

2005-01-01

369

Characterization of Behavioral and Neurodegenerative Changes Following Partial Lesions of the Nigrostriatal Dopamine System Induced by Intrastriatal 6Hydroxydopamine in the Rat  

Microsoft Academic Search

Partial lesions of the nigrostriatal dopamine system have been investigated with respect to their ability to induce consistent long-lasting deficits in movement initiation and skilled forelimb use. In eight different lesion groups 6-hydroxydopamine (6-OHDA) was injected at one, two, three, or four sites into the lateral sector of the right striatum, in a total dose of 20–30 ?g. Impairments in

Deniz Kirik; Carl Rosenblad; Anders Björklund

1998-01-01

370

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

Microsoft Academic Search

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

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

2007-01-01

371

Glutamate is not involved in the MPP + -induced dopamine overflow in the striatum of freely moving C57BL\\/6 mice  

Microsoft Academic Search

Summary.   The role of glutamate in the N-methyl-4-phenyl-dihydropyridinium (MPP+) toxicity has been argued in the past decade. However, the effects of glutamate efflux and NMDA antagonist on MPP+-induced dopamine overflow have not been documented. To clarify this, we perfused MPP+ through a microdialysis probe in the striatum of freely moving mature C57BL\\/6 mice. The 60-min perfusion of 10 and 100

T. Uezono; K. Matsubara; K. Shimizu; H. Mizukami; K. Ogawa; O. Saito; N. Hayase; H. Eto; K. Kimura; H. Shiono

2001-01-01

372

Observations of VLF transmitter-induced depletions of inner zone electrons  

SciTech Connect

Precipitation spikes of electrons, in which the energy spread of the peak is narrow (less than 50 keV) and the peak energy is a strong function of the location in L, have been observed in the region 1.5 < L < 2.0 and have been ascribed to interactions between waves from high power VLF transmitters on the ground and the precipitated electrons (Vampola and Kuck, 1978; Imhof et al., 1981). On numerous occasions when these spikes were observed at low altitude by instrumentation on the S3-2 satellite, a significant depletion of electrons at the same energies was observed high on the field line. These depletions indicate that the loss rate of electrons due to VLF transmitters is significant and usually exceeds the rate at which radial diffusion is refilling those field lines. Electrons with energies between 36 keV and 317 keV in the region 1.9 < L < 1.6 were observed to have lifetimes limited to a few days by interactions with waves from VLF transmitters. Thus the outer edge of the inner zone is defined by this wave-particle process.

Vampola, A.L.

1983-08-01

373

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 [¹?F]fallypride and [³H]-(+)-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

2012-06-13

374

Dopamine Oxidation and Autophagy  

PubMed Central

The molecular mechanisms involved in the neurodegenerative process of Parkinson's disease remain unclear. Currently, there is a general agreement that mitochondrial dysfunction, ?-synuclein aggregation, oxidative stress, neuroinflammation, and impaired protein degradation are involved in the neurodegeneration of dopaminergic neurons containing neuromelanin in Parkinson's disease. Aminochrome has been proposed to play an essential role in the degeneration of dopaminergic neurons containing neuromelanin by inducing mitochondrial dysfunction, oxidative stress, the formation of neurotoxic ?-synuclein protofibrils, and impaired protein degradation. Here, we discuss the relationship between the oxidation of dopamine to aminochrome, the precursor of neuromelanin, autophagy dysfunction in dopaminergic neurons containing neuromelanin, and the role of dopamine oxidation to aminochrome in autophagy dysfunction in dopaminergic neurons. Aminochrome induces the following: (i) the formation of ?-synuclein protofibrils that inactivate chaperone-mediated autophagy; (ii) the formation of adducts with ?- and ?-tubulin, which induce the aggregation of the microtubules required for the fusion of autophagy vacuoles and lysosomes.

Munoz, Patricia; Huenchuguala, Sandro; Paris, Irmgard; Segura-Aguilar, Juan

2012-01-01

375

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

376

Kainic acid-induced seizures modulate Akt (SER473) phosphorylation in the hippocampus of dopamine D2 receptor knockout mice.  

PubMed

Dopamine D2 receptor (D2R) signalling has been shown to modulate seizure-induced hippocampal cell death. D2R knockout (D2R-/-) mice are more susceptible to kainic acid (KA)-induced excitotoxicity, displaying cell death in the CA3 subfield of the hippocampus at KA doses not damaging in wild-type (WT) animals. Absence of D2R signalling in the hippocampus leads to activation (dephosphorylation) of glycogen synthase kinase 3? (GSK-3?) after KA (20 mg/kg), which is not associated with a change in the phosphorylation of the GSK-3? regulator Akt at the canonical threonine 308 residue. In the present study, we investigated alternative pathways responsible for the activation of GSK-3? in the hippocampus of the D2R-/- mice 24 h following KA-induced seizures. Here, we show that phosphorylation of Akt occurs at serine 473 (Ser473) in the CA3 region of WT but not D2R-/- mice following KA. Moreover, the CA1 subregion, which does not undergo neurodegeneration in either WT or D2R-/- mice, displays a strong induction of Akt (Ser473) phosphorylation after KA. Additionally, the vulnerability in the CA3 is not associated with changes to p38MAPK and Dishevelled activation, and ?-catenin does not appear to be a downstream target of the GSK-3?. Thus, we propose that GSK-3? phosphorylation-mediated hippocampal cell survival may depend on Akt (Ser473) phosphorylation; loss of D2R-mediated signalling in the CA3 region of D2R-/- mice leads to reduced Akt (Ser473) phosphorylation rendering neurons more vulnerable to apoptosis. Further investigation is required to fully elucidate the GSK-3? targets involved in D2R-dependent response to excitotoxicity. PMID:23188702

Dunleavy, Mark; Provenzano, Giovanni; Henshall, David C; Bozzi, Yuri

2012-11-29

377

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

378

Clonidine and guanfacine attenuate phencyclidine-induced dopamine overflow in rat prefrontal cortex: mediating influence of the alpha-2A adrenoceptor subtype.  

PubMed

N-methyl-D-aspartic acid/glutamate receptor antagonists induce psychotomimetic effects in humans and animals, and much research has focused on the neurochemical and network-level effects that mediate those behavioral changes. For example, a reduction in NMDA-dependent glutamatergic transmission triggers increased release of the monoamine transmitters, and some of these changes are implicated in the cognitive, behavioral and neuroanatomical effects of phencyclidine (PCP). Alpha-2 adrenoceptor agonists (e.g., clonidine) are effective at preventing many of the behavioral, neurochemical and anatomical effects of NMDA antagonists. Evidence has indicated that a key mechanism of the clonidine-induced reversal of the effects of NMDA antagonists is an attenuation of enhanced dopamine release. We have pursued these findings by investigating the effects of alpha-2 agonists on PCP-evoked dopamine efflux in the prefrontal cortex of freely moving rats. Clonidine (0.003-0.1 mg/kg, i.p.) dose-dependently attenuated the ability of PCP (2.5 mg/kg, i.p.) to increase cortical dopamine output. The effects of clonidine were prevented by the alpha-2A subtype selective antagonist BRL-44408 (1 mg/kg, i.p.). Guanfacine, which is an alpha-2 agonist with a higher affinity for the 2A, compared with 2B or 2C, subtypes, also blocked the ability of PCP to increase dopamine efflux in the prefrontal cortex. These data indicate that alpha-2A agonists are effective at counteracting the hyperdopaminergic state induced by PCP and may play a role in their neurobehavioral effects in this putative animal model for schizophrenia. PMID:18977208

Jentsch, J David; Sanchez, Diana; Elsworth, John D; Roth, Robert H

2008-10-18

379

AC927, a ? receptor ligand, blocks methamphetamine-induced release of dopamine and generation of reactive oxygen species in NG108-15 cells.  

PubMed

Methamphetamine is a highly addictive psychostimulant drug of abuse that causes neurotoxicity with high or repeated dosing. Earlier studies demonstrated the ability of the selective ? receptor ligand N-phenethylpiperidine oxalate (AC927) to attenuate the neurotoxic effects of methamphetamine in vivo. However, the precise mechanisms through which AC927 conveys its protective effects remain to be determined. With the use of differentiated NG108-15 cells as a model system, the effects of methamphetamine on neurotoxic endpoints and mediators such as apoptosis, necrosis, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and dopamine release were examined in the absence and presence of AC927. Methamphetamine at physiologically relevant micromolar concentrations caused apoptosis in NG108-15 cells. At higher concentrations of methamphetamine, necrotic cell death was observed. At earlier time points, methamphetamine caused ROS/RNS generation, which was detected with the fluorigenic substrate 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescin diacetate, acetyl ester, in a concentration- and time-dependent manner. N-Acetylcysteine, catalase, and l-N(G)-monomethyl arginine citrate inhibited the ROS/RNS fluorescence signal induced by methamphetamine, which suggests the formation of hydrogen peroxide and RNS. Exposure to methamphetamine also stimulated the release of dopamine from NG108-15 cells into the culture medium. AC927 attenuated methamphetamine-induced apoptosis, necrosis, ROS/RNS generation, and dopamine release in NG108-15 cells. Together, the data suggest that modulation of ? receptors can mitigate methamphetamine-induced cytotoxicity, ROS/RNS generation, and dopamine release in cultured cells. PMID:22101517

Kaushal, Nidhi; Elliott, Meenal; Robson, Matthew J; Iyer, Anand Krishnan V; Rojanasakul, Yon; Coop, Andrew; Matsumoto, Rae R

2011-11-18

380

Involvement of canonical and non-canonical D1 dopamine receptor signalling pathways in L-dopa-induced dyskinesia.  

PubMed

Chronic L-3,4-dihydroxyphenylalanine (L-dopa) treatment of Parkinson Disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID). The past few years have seen an unprecedented increase in understanding the neural mechanisms underlying LID manifestation in PD associating them mostly with D1 dopamine (DA) receptor sensitisation and deregulated homologous desensitisation as well as hyperactivity of both canonical and non-canonical DA signalling pathways. We here review these recent findings and demonstrate that decreasing DA receptor-mediated signalling (i) by increasing D1 receptor internalization and (ii) by inhibiting the Ras-Extracellular signal-Regulated Kinase 1/2 non-canonical DA signalling cascade, might reduced LID severity. Strategy (i) uses the lentivirus-mediated over-expression of the G protein-coupled receptor kinase 6 that control the desensitisation of DA receptors. Strategy (ii) proposes to use statins that, besides being specific inhibitors of the rate-limiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity and subsequently the phosphorylation of ERK1/2. Experiments were performed in both the rodent and primate models of LID. Those results strongly suggest that different strategies might represent a treatment option for managing LID in PD. PMID:20083011

Guigoni, Céline; Bezard, Erwan

2009-12-01

381

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

382

Forward genetic analysis to identify determinants of dopamine signaling in Caenorhabditis elegans using swimming-induced paralysis.  

PubMed

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

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

2012-08-01

383

Naloxone-blocked depriming effect of anxiolytic selank on apomorphine-induced behavioral manifestations of hyperfunction of dopamine system.  

PubMed

Peptide anxiolytic selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) applied intraperitoneally in doses of 0.01, 0.1, 1.0, and 10.0 mg/kg to mice reduces behavioral manifestations of dopaminergic system induced by apomorphine in the verticalization test. This effect was comparable to that of atypical antipsychotic olanzapine in near-therapeutic doses (0.1 and 1.0 mg/kg, intraperitoneally) and was blocked with nonselective opioid receptor antagonist naloxone (10 mg/kg, intraperitoneally). Radioreceptor assay showed that selank did not displace nonselective D2-dopamine receptor antagonist (3)H-spiperone (EC50>100 microM) and delta- and micro-opioid receptor ligand 3H-DADLE (EC50>40 microM) from specific binding sites on rat brain membranes. It is hypothesized that the revealed behavioral effect of selank is mediated by its modulating effect on the endogenous opioid system and specifically, by its effect on activity of enkephalin-degrading enzymes. PMID:17415472

Meshavkin, V K; Kost, N V; Sokolov, O Yu; Zolotarev, Yu A; Myasoedov, N F; Zozulya, A A

2006-11-01

384

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

PubMed Central

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

Karentz, D

1994-01-01

385

Numerical modeling of self-limiting and self-enhancing caprock alteration induced by CO2 storage in a depleted gas reservoir  

Microsoft Academic Search

This paper presents numerical simulations of reactive transport which may be induced in the caprock of an on-shore depleted gas reservoir by the geological sequestration of carbon dioxide. The objective is to verify that CO geological disposal activities currently being planned for the study area are safe and do not induce any undesired environmental impact. In our model, fluid flow

Tianfu Xu; Fabrizio Gherardi; Karsten Pruess

2007-01-01

386

Comparison of phenethyl and 6-phenylhexyl isothiocyanate-induced toxicity in rat esophageal cell lines with and without glutathione depletion.  

PubMed

Phenethyl isothiocyanate (PEITC) and its synthetic homolog, 6-phenylhexyl isothiocyanate (PHITC), are both potent inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung mice tumorigenesis. However, unlike PEITC, PHITC enhanced N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis. These findings imply that due to its unique chemical properties, PHITC's effects on esophageal cells are procarcinogenic rather than chemopreventive. Relative to PEITC, PHITC is more lipophilic and less reactive, which could result in higher PHITC intracellular levels. Due to ITCs' inherently high level of thiol reactivity, increased intracellular levels of PHITC have the potential to deplete intracellular glutathione (GSH) reserves. Since GSH is a primary intracellular antioxidant and cytoprotective enzyme cofactor, preservation of intracellular GSH status is crucial for cytoprotection. Despite the recognized importance of isothiocyanate structure with the potential for toxicity, no studies have yet investigated the association between the primary intracellular free thiol, GSH, and isothiocyanate-induced toxicity in this target cell population. The present study investigated whether PEITC and PHITC display unique cytotoxic profiles in cultured rat esophageal cells, and also monitored the effects of ITC challenge on cellular GSH status. A final series of experiments investigated the converse i.e., affects of modulation of intracellular GSH status on ITC-mediated toxicity. Dose-response curves revealed that PEITC was significantly more toxic in tumorigenic and non-tumorigenic cells relative to PHITC. The ITC-GSH interaction studies demonstrated comparable GSH levels following either PEITC or PHITC challenge, and also showed that GSH depletion did not augment ITC-mediated cellular toxicity. While our data demonstrate structure related differences in ITC-mediated cytotoxicities, these differences do not appear to be directly attributable to cellular GSH pools. PMID:15649627

Hudson, Tamaro S; Stoner, Gary D; Morse, Mark A; Young, Heather; Mallery, Susan R

2005-03-15

387

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

388

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

389

Glutathione Depletion, Lipid Peroxidation and Mitochondrial Dysfunction Are Induced by Chronic Stress in Rat Brain  

Microsoft Academic Search

Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurodegenerative disorders. We have previously demonstrated that chronic stress induced an increase in nitric oxide (NO) production via an expression of inducible NO synthase (iNOS) in brain. Since it has been demonstrated that NO regulates mitochondrial function, we

Jose LM Madrigal; Raquel Olivenza; Maria A Moro; Ignacio Lizasoain; Pedro Lorenzo; Jose Rodrigo; Juan C Leza

2001-01-01

390

Reversal of methamphetamine-induced behavioral sensitization by repeated administration of a dopamine D 1 receptor agonist  

Microsoft Academic Search

Repeated intermittent administration of methamphetamine (MAP) produces an enduring hypersensitivity to the motor stimulant effect of MAP, termed behavioral sensitization. Dopamine plays a critical role in the development and expression of behavioral sensitization. Here, we investigated whether a dopamine D1 receptor agonist could reverse behavioral sensitization to MAP. Administration of MAP (1.0mg\\/kg, i.p.) to rats once every 3days for a

Takahide Shuto; Mahomi Kuroiwa; Mitsuko Hamamura; Kenichi Yabuuchi; Takao Shimazoe; Shigenori Watanabe; Akinori Nishi; Tsuneyuki Yamamoto

2006-01-01

391

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

392

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 neurotransmiss