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Teresa G Hastings - One of the best experts on this subject based on the ideXlab platform.
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Modification of Dopamine transporter function : Effect of reactive oxygen species and Dopamine
Journal of Neurochemistry, 2002Co-Authors: Sarah B. Berman, Michael J. Zigmond, Teresa G HastingsAbstract:: Dopamine can oxidize to form reactive oxygen species and quinones, and we have previously shown that Dopamine quinones bind covalently to cysteinyl residues on striatal proteins. The Dopamine transporter is one of the proteins at risk for this modification, because it has a high affinity for Dopamine and contains several cysteinyl residues. Therefore, we tested whether Dopamine transport in rat striatal synaptosomes could be affected by generators of reactive oxygen species, including Dopamine. Uptake of [3H]Dopamine (250 nM) was inhibited by ascorbate (0.85 mM; -44%), and this inhibition was prevented by the iron chelator diethylenetriaminepentaacetic acid (1 mM), suggesting that ascorbate was acting as a prooxidant in the presence of iron. Preincubation with xanthine (500 microM) and xanthine oxidase (50 mU/ml) also reduced [3H]Dopamine uptake (-76%). Preincubation with Dopamine (100 microM) caused a 60% inhibition of subsequent [3H]Dopamine uptake. This Dopamine-induced inhibition was attenuated by diethylenetriaminepentaacetic acid (1 mM), which can prevent iron-catalyzed oxidation of Dopamine during the preincubation, but was unaffected by the monoamine oxidase inhibitor pargyline (10 microM). None of these incubations caused a loss of membrane integrity as indicated by lactate dehydrogenase release. These findings suggest that reactive oxygen species and possibly Dopamine quinones can modify Dopamine transport function.
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Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria implications for parkinson s disease
Journal of Neurochemistry, 2001Co-Authors: Sarah B. Berman, Teresa G HastingsAbstract:Abstract : Both reactive Dopamine metabolites and mitochondrial dysfunction have been implicated in the neurodegeneration of Parkinson’s disease. Dopamine metabolites, Dopamine quinone and reactive oxygen species, can directly alter protein function by oxidative modifications, and several mitochondrial proteins may be targets of this oxidative damage. In this study, we examined, using isolated brain mitochondria, whether Dopamine oxidation products alter mitochondrial function. We found that exposure to Dopamine quinone caused a large increase in mitochondrial resting state 4 respiration. This effect was prevented by GSH but not superoxide dismutase and catalase. In contrast, exposure to Dopamine and monoamine oxidase-generated hydrogen peroxide resulted in a decrease in active state 3 respiration. This inhibition was prevented by both pargyline and catalase. We also examined the effects of Dopamine oxidation products on the opening of the mitochondrial permeability transition pore, which has been implicated in neuronal cell death. Dopamine oxidation to Dopamine quinone caused a significant increase in swelling of brain and liver mitochondria. This was inhibited by both the pore inhibitor cyclosporin A and GSH, suggesting that swelling was due to pore opening and related to Dopamine quinone formation. In contrast, Dopamine and endogenous monoamine oxidase had no effect on mitochondrial swelling. These findings suggest that mitochondrial dysfunction induced by products of Dopamine oxidation may be involved in neurodegenerative conditions such as Parkinson’s disease and methamphetamine-induced neurotoxicity.
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Role of oxidative changes in the degeneration of Dopamine terminals after injection of neurotoxic levels of Dopamine.
Neuroscience, 2000Co-Authors: A.d Rabinovic, David A. Lewis, Teresa G HastingsAbstract:Abstract Dopamine may contribute to the loss of Dopamine neurons in Parkinson’s disease by generating reactive oxygen species and quinones. A previous report from this laboratory showed that intrastriatal injection of Dopamine resulted in the selective reduction of tyrosine hydroxylase immunoreactivity, accompanied by an increase in indices of Dopamine oxidation. However, conclusive proof that decreased tyrosine hydroxylase immunoreactivity represented a loss of Dopamine terminals was lacking. In this paper, we demonstrate that injection of Dopamine results in a selective loss of Dopamine terminals by (i) showing that immunoreactivity for another selective marker for Dopamine terminals, the Dopamine transporter, is also reduced; and (ii) that amino-cupric-silver stain reveals terminal degeneration within the area of selective loss of Dopamine terminals. To determine the Dopamine concentration that is selectively toxic to Dopamine terminals, we examined changes in extracellular Dopamine and 3,4-dihydroxyphenylacetic acid in the area of selective terminal loss following intrastriatal Dopamine. Dopamine and 3,4-dihydroxyphenylacetic acid in this region reached peak levels 1–2 h after the injection, and then returned towards baseline. The peak level of Dopamine in the area of selective Dopamine terminal damage was 10 2 –10 3 -fold lower than the injected concentration. Changes in striatal tissue levels of cysteinyl-catechols and glutathione were examined at 2, 4, 8, and 24 h after intrastriatal Dopamine. Levels of protein cysteinyl-Dopamine and cysteinyl-3,4-dihydroxyphenylacetic acid were increased at all time-points following the Dopamine injection. High levels of free cysteinyl-catechols and glutathione-Dopamine were detected within 2 h after the Dopamine injection. Glutathione levels were decreased significantly at 4 and 8 h after the injection of Dopamine, and returned to control levels by 24 h. These data indicate that Dopamine terminals actively degenerate following a single intrastriatal injection of Dopamine, and furthermore that oxidative stress plays a key role in this process. As oxidative stress is thought to play an active role in the pathobiology of Parkinson’s disease, these data may be relevant to our understanding of the disorder.
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Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine evidence against a role for extracellular Dopamine
The Journal of Neuroscience, 1999Co-Authors: Matthew J. Lavoie, Teresa G HastingsAbstract:Methamphetamine-induced toxicity has been shown to require striatal Dopamine and to involve mechanisms associated with oxidative stress. Dopamine is a reactive molecule that can oxidize to form free radicals and reactive quinones. Although this has been suggested to contribute to the mechanism of toxicity, the oxidation of Dopamine has never been directly measured after methamphetamine exposure. In this study we sought to determine whether methamphetamine-induced toxicity is associated with the oxidation of Dopamine by measuring the binding of Dopamine quinones to cysteinyl residues on protein. We observed that administration of neurotoxic doses of methamphetamine to rats resulted in a two- to threefold increase in protein cysteinyl-Dopamine in the striatum 2, 4, and 8 hr after treatment. When methamphetamine was administered at an ambient temperature of 5°C, no increase in Dopamine oxidation products was observed, and toxicity was prevented. Furthermore, as shown by striatal microdialysis, animals treated with methamphetamine at 5°C showed DA release identical to that of animals treated at room temperature. These data suggest that the toxicity of methamphetamine and the associated increase in Dopamine oxidation are not exclusively the result of increases in extracellular Dopamine. Because Dopamine-induced modifications of protein structure and function may result in cellular toxicity, it is likely that Dopamine oxidation contributes to methamphetamine-induced toxicity to Dopamine terminals, adding support to the role of Dopamine and the evidence of oxidative stress in this lesion model.
121–136. Http://doi.org/10.1007/s11571-008-9038-0 Kiebel, S. J., Garrido, M. I., Moran, R. J., & Fri - One of the best experts on this subject based on the ideXlab platform.
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Dopamine in schizophrenia: a review and reconceptualization
Am J Psychiatry, 1991Co-Authors: 148–155. Http://doi.org/citeulike-article-id:3687170 Doi: 10.1016/j.schres.2007.04.023 Gold, J. M., Fuller, R. L., Robinson, B. M., Braun, A. P. (1995). Statistical Parametric Maps In Functional Imaging. Friston, K. J., & Holmes, 590–601. Http://doi.org/10.1016/j.neuroimage.2009.04.062 Daunizeau, J., Kiebel, S. J., & Friston, K. J. (20, 311–317. Http://doi.org/10.1038/335311a0 Zeki, S., & Shipp, S. (1988). The Functional Logic, 55–65. Http://doi.org/10.1016/j.schres.2004.10.011 Kim, D., Zemon, V., Saperstein, A., Butler, P. D.,, 2322–2329. Http://doi.org/10.1016/j.neuroimage.2011.09.025 Lohmann, G., Erfurth, K., Muller, K., & Turner, R., 1610–1624. Tootell, R. B., Silverman, M. S., Hamilton, S. L.,, 1442–1451. Http://doi.org/10.1016/j.clinph.2004.01.019 Fuchs, M., Wagner, M., & Kastner, J. (2004). Confi, 121–136. Http://doi.org/10.1007/s11571-008-9038-0 Kiebel, S. J., Garrido, M. I., Moran, R. J., & FriAbstract:OBJECTIVE: The initial hypothesis that schizophrenia is a manifestation of hyperDopaminergia has recently been faulted. However, several new findings suggest that abnormal, although not necessarily excessive, Dopamine activity is an important factor in schizophrenia. The authors discuss these findings and their implications. METHOD: All published studies regarding Dopamine and schizophrenia and all studies on the role of Dopamine in cognition were reviewed. Attention has focused on post-mortem studies, positron emission tomography, neuroleptic drug actions, plasma levels of the Dopamine metabolite homovanillic acid (HVA), and cerebral blood flow. RESULTS: Evidence, particularly from intracellular recording studies in animals and plasma HVA measurements, suggests that neuroleptics act by reducing Dopamine activity in mesolimbic Dopamine neurons. Post-mortem studies have shown high Dopamine and HVA concentrations in various subcortical brain regions and greater than normal Dopamine receptor densities in the brains of schizophrenic patients. On the other hand, the negative/deficit symptom complex of schizophrenia may be associated with low Dopamine activity in the prefrontal cortex. Recent animal and human studies suggest that prefrontal Dopamine neurons inhibit subcortical Dopamine activity. The authors hypothesize that schizophrenia is characterized by abnormally low prefrontal Dopamine activity (causing deficit symptoms) leading to excessive Dopamine activity in mesolimbic Dopamine neurons (causing positive symptoms). CONCLUSIONS: The possible co-occurrence of high and low Dopamine activity in schizophrenia has implications for the conceptualization of Dopamine's role in schizophrenia. It would explain the concurrent presence of negative and positive symptoms. This hypothesis is testable and has important implications for treatment of schizophrenia and schizophrenia spectrum disorders.
Regina M Carelli - One of the best experts on this subject based on the ideXlab platform.
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Sources contributing to the average extracellular concentration of Dopamine in the nucleus accumbens
Journal of Neurochemistry, 2012Co-Authors: Catarina A. Owesson-white, Leslie A. Sombers, Anna M. Belle, Richard B. Keithley, Jessica L. Peele, Regina M Carelli, Mitchell F. Roitman, R. Mark WightmanAbstract:J. Neurochem. (2012) 121, 252–262. Abstract Mesolimbic Dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of Dopamine in the nucleus accumbens (NAc). In the past, different techniques have targeted Dopamine levels in the NAc to establish a basal concentration. In this study, we used in vivo fast scan cyclic voltammetry (FSCV) in the NAc of awake, freely moving rats. The experiments were primarily designed to capture changes in Dopamine caused by phasic firing – that is, the measurement of Dopamine ‘transients’. These FSCV measurements revealed for the first time that spontaneous Dopamine transients constitute a major component of extracellular Dopamine levels in the NAc. A series of experiments were designed to probe regulation of extracellular Dopamine. Lidocaine was infused into the ventral tegmental area, the site of Dopamine cell bodies, to arrest neuronal firing. While there was virtually no instantaneous change in Dopamine concentration, longer sampling revealed a decrease in Dopamine transients and a time-averaged decrease in the extracellular level. Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular Dopamine levels changing both frequency and size of Dopamine transients in the NAc. To further unmask the mechanics governing extracellular Dopamine levels we used intravenous injection of the vesicular monoamine transporter (VMAT2) inhibitor, tetrabenazine, to deplete Dopamine storage and increase cytoplasmic Dopamine in the nerve terminals. Tetrabenazine almost abolished phasic Dopamine release but increased extracellular Dopamine to ∼500 nM, presumably by inducing reverse transport by Dopamine transporter (DAT). Taken together, data presented here show that average extracellular Dopamine in the NAc is low (20–30 nM) and largely arises from phasic Dopamine transients.
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Subsecond Dopamine release promotes cocaine seeking
Nature, 2003Co-Authors: Paul E M Phillips, Michael L A V Helen, Garret D. Stuber, R. Mark Wightman, Regina M CarelliAbstract:The Dopamine-containing projection from the ventral tegmental area of the midbrain to the nucleus accumbens is critically involved in mediating the reinforcing properties of cocaine. Although neurons in this area respond to rewards on a subsecond timescale, neurochemical studies have only addressed the role of Dopamine in drug addiction by examining changes in the tonic (minute-to-minute) levels of extracellular Dopamine. To investigate the role of phasic (subsecond) Dopamine signalling, we measured Dopamine every 100 ms in the nucleus accumbens using electrochemical technology. Rapid changes in extracellular Dopamine concentration were observed at key aspects of drug-taking behaviour in rats. Before lever presses for cocaine, there was an increase in Dopamine that coincided with the initiation of drug-seeking behaviours. Notably, these behaviours could be reproduced by electrically evoking Dopamine release on this timescale. After lever presses, there were further increases in Dopamine concentration at the concurrent presentation of cocaine-related cues. These cues alone also elicited similar, rapid Dopamine signalling, but only in animals where they had previously been paired to cocaine delivery. These findings reveal an unprecedented role for Dopamine in the regulation of drug taking in real time.
Anthony A Grace - One of the best experts on this subject based on the ideXlab platform.
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Afferent modulation of Dopamine neuron firing differentially regulates tonic and phasic Dopamine transmission
Nature Neuroscience, 2003Co-Authors: Stan B Floresco, Holly Moorel, B Ash, Anthony R. West, Anthony A GraceAbstract:The mesolimbic Dopamine system is centrally involved in reward and goal-directed behavior, and it has been implicated in multiple psychiatric disorders. Understanding the mechanism by which Dopamine participates in these activities requires comprehension of the dynamics of Dopamine release. Here we report dissociable regulation of Dopamine neuron discharge by two separate afferent systems in rats; inhibition of pallidal afferents selectively increased the population activity of Dopamine neurons, whereas activation of pedunculopontine inputs increased burst firing. Only the increase in population activity increased ventral striatal Dopamine efflux. After blockade of Dopamine reuptake, however, enhanced bursting increased Dopamine efflux three times more than did enhanced population activity. These results provide insight into multiple regulatory systems that modulate Dopamine system function: burst firing induces massive synaptic Dopamine release, which is rapidly removed by reuptake before escaping the synaptic cleft, whereas increased population activity modulates tonic extrasynaptic Dopamine levels that are less influenced by reuptake.
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Partial Dopamine depletions result in an enhanced sensitivity of residual Dopamine neurons to apomorphine.
Synapse, 1991Co-Authors: Michele L. Pucak, Anthony A GraceAbstract:: Extracellular recordings from identified Dopamine neurons were used to assess the effect of 6-hydroxyDopamine-induced partial lesions of the nigrostriatal Dopamine system on the sensitivity of the residual Dopamine neurons to the Dopamine agonist apomorphine. This was done by testing the response of identified nigral Dopamine neurons in control and lesioned rats to systemic apomorphine administration at two time points: 1) 6-10 days post-lesion, when the loss of Dopamine cells is nearly complete, and 2) 4-8 weeks post-lesion, which should be sufficient time for changes in Dopamine receptor density to occur. As reported previously, Dopamine neurons in control rats were inhibited by systemic administration of apomorphine, with their sensitivity being inversely related to their initial firing rate. The sensitivity of the residual Dopamine neurons to apomorphine was unaltered in rats tested 6-10 days after depletions of at least 60% of striatal Dopamine. However, by 4-8 weeks post-lesion, there was a significant increase in the sensitivity to apomorphine; furthermore, sensitivity was no longer related to baseline firing rate, but instead was uniformly high in all Dopamine neurons tested at this time. This enhanced sensitivity was not altered by hemisection of the striatonigral projection, suggesting that the increased sensitivity to apomorphine was most likely a result of a time-dependent up-regulation of somatodendritic autoreceptors on the residual Dopamine neurons.
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Phasic versus tonic Dopamine release and the modulation of Dopamine system responsivity: A hypothesis for the etiology of schizophrenia
Neuroscience, 1991Co-Authors: Anthony A GraceAbstract:A novel mechanism for regulating Dopamine activity in subcortical sites and its possible relevance to schizophrenia is proposed. This hypothesis is based on the regulation of Dopamine release into subcortical regions occurring via two independent mechanisms: 1. (1) transient or phasic Dopamine release caused by Dopamine neuron firing, and 2. (2) sustained, "background" tonic Dopamine release regulated by prefrontal cortical afferents. Behaviorally relevant stimuli are proposed to cause short-term activation of Dopamine cell firing to trigger the phasic component of Dopamine release. In contrast, tonic Dopamine release is proposed to regulate the intensity of the phasic Dopamine response through its effect on extracellular Dopamine levels. In this way, tonic Dopamine release would set the background level of Dopamine receptor stimulation (both autoreceptor and postsynaptic) and, through homeostatic mechanisms, the responsivity of the system to Dopamine in these sites. In schizophrenics, a prolonged decrease in prefrontal cortical activity is proposed to reduce tonic Dopamine release. Over time, this would elicit homeostatic compensations that would increase overall Dopamine responsivity and thereby cause subsequent phasic Dopamine release to elicit abnormally large responses. © 1991.
Pierre Maechler - One of the best experts on this subject based on the ideXlab platform.
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minireview new roles for peripheral Dopamine on metabolic control and tumor growth let s seek the balance
Endocrinology, 2010Co-Authors: Blanca Rubi, Pierre MaechlerAbstract:In peripheral tissues, Dopamine is released from neuronal cells and is synthesized within specific parenchyma. Dopamine released from sympathetic nerves predominantly contributes to plasma Dopamine levels. Despite growing evidence for peripheral source and action of Dopamine and the widespread expression of Dopamine receptors in peripheral tissues, most studies have focused on functions of Dopamine in the central nervous system. Symptoms of several brain disorders, including schizophrenia, Parkinson’s disease, attention-deficit hyperactivity disorder, and depression, are alleviated by pharmacological modulation of Dopamine transmission. Regarding systemic disorders, the role of Dopamine is still poorly understood. Here we describe the pioneering and recent evidence for functional roles of peripheral Dopamine. Peripheral and central Dopamine systems are sensitive to environmental stress, such as a high-fat diet, suggesting a basis of covariance of peripheral and central actions of Dopaminergic agents. Give...
