Altered striatal dopamine release following a sub-acute exposure to manganese
Department of Chemistry, Wayne State University, 5101 Cass Ave., Detroit, MI 48202, USA. Journal of Neuroscience Methods
(Impact Factor: 2.05).
06/2011; 202(2):182-91. DOI: 10.1016/j.jneumeth.2011.06.019
Certain metals that are necessary for regulating biological function at trace levels hold the potential to become neurotoxic when in excess. Specifically, chronic exposure to high levels of manganese leads to manganism, a neurological disorder that exhibits both motor and learning deficits similar to Parkinson's disease. Since Parkinson's disease symptomatology is primarily attributed to dopamine neurodegeneration in the striatum, dopamine system dysfunction has been implicated in the onset of manganism. In this study, dopamine system function in the dorsal striatum was evaluated in C57Bl/6 mice, 1, 7, and 21 days following repeated injections of manganese(II) chloride (50 mg/kg, subcutaneous) intermittently for 7 days. Tissue content analysis confirmed the presence of persistent accumulation of manganese in the striatum up to 21 days after cessation of treatment. In vitro fast scan cyclic voltammetry examined the effect of sub-acute manganese on electrically stimulated dopamine release and uptake in the striatum. While no difference was observed in uptake rates following manganese treatment, dopamine release was attenuated on days 7 and 21, compared to control levels. Basal levels of extracellular dopamine determined by the zero net flux microdialysis method were significantly lower in manganese-treated mice at 7 days post-treatment. On the other hand, potassium stimulated increases in extracellular dopamine were attenuated at all three time points. Together, these findings indicate that repeated manganese exposure has long-term effects on the regulation of exocytotic dopamine release in the striatum, which may be involved in the mechanism underlying manganese toxicity.
Available from: toxsci.oxfordjournals.org
- "These observed beneficial effects of chelation therapy may be associated with cellular or molecular processes that are inhibited only in the presence of Mn, rather than by frank neurodegeneration. From this perspective, Mn inhibition of striatal dopamine release, which has been documented in Mn exposed nonhuman primates (Guilarte et al., 2006, 2008) and rodents (Khalid et al., 2011), may be reversible if brain Mn levels are reduced. PET studies of in vivo dopamine release in human subjects with the SLC30A10 mutation, as well as in other human conditions of Mn intoxication, can assist in defining the relationship between chelation therapy-induced reversibility of movement abnormalities and Mn-induced inhibition of striatal dopamine release. "
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ABSTRACT: Movement abnormalities caused by chronic manganese (Mn) intoxication clinically resemble but are not identical to those in idiopathic Parkinson's disease. In fact, the most successful parkinsonian drug treatment, the dopamine precursor levodopa, is ineffective in alleviating Mn-induced motor symptoms, implying that parkinsonism in Mn-exposed individuals may not be linked to midbrain dopaminergic neuron cell loss. Over the last decade, supporting evidence from human and nonhuman primates has emerged that Mn-induced parkinsonism partially results from damage to basal ganglia nuclei of the striatal "direct pathway" (ie, the caudate/putamen, internal globus pallidus, and substantia nigra pars reticulata) and a marked inhibition of striatal dopamine release in the absence of nigrostriatal dopamine terminal degeneration. Recent neuroimaging studies have revealed similar findings in a particular group of young drug users intravenously injecting the Mn-containing psychostimulant ephedron and in individuals with inherited mutations of the Mn transporter gene SLC30A10. This review will provide a detailed discussion about the aforementioned studies, followed by a comparison with their rodent analogs and idiopathic parkinsonism. Together, these findings in combination with a limited knowledge about the underlying neuropathology of Mn-induced parkinsonism strongly support the need for a more complete understanding of the neurotoxic effects of Mn on basal ganglia function to uncover the appropriate cellular and molecular therapeutic targets for this disorder.
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Available from: Stefanie O'Neal
- "For example, many researchers utilize C57 mice in their studies. Some investigators observed a decrease in striatal DA (Gianutsos and Murray, 1982; Khalid et al., 2011; Madison et al., 2012), and some do not observe a change in striatal DA (Dodd et al., 2013). It seems plausible that the sex of the animal may also play a role in the outcome of studies of Mn exposure on neurochemistry, as females have been found to exhibit increased Mn absorption relative to males (Dobson et al., 2004). "
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ABSTRACT: Manganese (Mn) is an essential trace element, but excess exposure leads to accumulation in biological tissues, including the brain. Chronically high Mn levels in the brain are neurotoxic and can result in a progressive, irreversible neurological disorder known as manganism. Manganism has signs and symptoms similar to, but distinguishable from idiopathic Parkinson's disease, which include both psychological and motor disturbances. Evidence suggests that Mn exposure impacts neurotransmitter levels in the brain. However, it remains unclear if subacute, low-level Mn exposure resulted in alterations in neurotransmitter systems with concomitant behavioral deficits. The current study used high performance liquid chromatography to quantify neurotransmitter levels in rat striatum (STR), substantia nigra (SN), and hippocampus (HP). Subacute Mn exposure via i.p. injection of 15mg Mn/kg as MnCl2 caused significantly increased dopamine (DA) levels in the STR. The enhancement was accompanied by significantly elevated levels of the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the STR. In addition, levels of HVA were significantly increased in the SN and HP. These data indicate that subacute, low-level Mn exposure disrupts multiple neurotransmitter systems in the rat brain which may be responsible, in part, for observed locomotor deficits.
Available from: Michelle L Colombo
- "The quantitative microdialysis technique of zero net flux was employed to determine basal extracellular dopamine levels as previously described (Lonnroth et al. 1987, Mathews et al. 2004, Khalid et al. 2011). After three baseline dialysis samples were collected with normal aCSF, perfusate containing 5, 10, and 20 nM dopamine (prepared in aCSF with 200 μM ascorbic acid) was delivered through the microdialysis probe for 90 min each using a CMA/ 402 programmable gradient infusion pump. "
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ABSTRACT: J. Neurochem. (2012) 120, 385–395.
Brain-derived neurotrophic factor (BDNF) modulates the synaptic transmission of several monoaminergic neuronal systems, including forebrain dopamine-containing neurons. Recent evidence shows a strong correlation between neuropsychiatric disorders and BDNF hypofunction. The aim of the present study was to characterize the effect of low endogenous levels of BDNF on dopamine system function in the caudate-putamen using heterozygous BDNF (BDNF+/−) mice. Apparent extracellular dopamine levels in the caudate-putamen, determined by quantitative microdialysis, were significantly elevated in BDNF+/− mice compared with wildtype controls (12 vs. 5 nM, respectively). BDNF+/− mice also had a potentiated increase in dopamine levels following potassium (120 mM)-stimulation (10-fold) relative to wildtype controls (6-fold). Slice fast-scan cyclic voltammetry revealed that BDNF+/− mice had reductions in both electrically evoked dopamine release and dopamine uptake rates in the caudate-putamen. Superfusion of BDNF led to partial recovery of the electrically stimulated dopamine release response in BDNF+/− mice. Conversely, tissue accumulation of L-3,4-dihydroxyphenylalanine, extracellular levels of dopamine metabolites, and spontaneous locomotor activity were unaltered. Together, this study indicates that endogenous BDNF influences dopamine system homeostasis by regulating the release and uptake dynamics of pre-synaptic dopamine transmission.
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