Altered striatal dopamine release following a sub-acute exposure to manganese.
ABSTRACT 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.
- SourceAvailable from: Anubhuti Dixit[Show abstract] [Hide abstract]
ABSTRACT: Rodent models and molecular tools, mainly omics and RNA interference, have been rigorously used to decode the intangible etiology and pathogenesis of Parkinson's disease (PD). Although convention of contemporary molecular techniques and multiple rodent models paved imperative leads in deciphering the role of putative causative factors and sequential events leading to PD, complete and clear-cut mechanisms of pathogenesis are still hard to pin down. The current article reviews the implications and pros and cons of rodent models and molecular tools in understanding the molecular and cellular bases of PD pathogenesis based on the existing literature. Probable rationales for short of comprehensive leads and future possibilities in spite of the extensive applications of molecular tools and rodent models have also been discussed.Molecular Neurobiology 06/2012; 46(2):495-512. · 5.47 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Administering manganese chloride (Mn) to rats on postnatal day (PD) 1-21 causes long-term reductions in dopamine transporter levels in the dorsal striatum, as well as persistent increases in D1 and D2 receptor concentrations. Whether dopamine autoreceptors change in number or sensitivity is uncertain, although D2S receptors, which may be presynaptic in origin, are elevated in Mn-exposed rats. The purpose of this study was to determine if early Mn exposure causes long-term changes in dopamine autoreceptor sensitivity that persist into adolescence and adulthood. To this end, male rats were exposed to Mn on PD 1-21 and autoreceptor functioning was tested 7 or 70 days later by measuring (a) dopamine synthesis (i.e., DOPA accumulation) in the dorsal striatum after quinpirole or haloperidol treatment and (b) behavioral responsiveness after low-dose apomorphine treatment. Results showed that low doses (i.e., "autoreceptor" doses) of apomorphine (0.06 and 0.12mg/kg) decreased the locomotor activity of adolescent and adult rats, while higher doses increased locomotion. The dopamine synthesis experiment also produced classic autoreceptor effects, because quinpirole decreased dorsal striatal DOPA accumulation; whereas, haloperidol increased DOPA levels in control rats, but not in rats given the nerve impulse inhibitor γ-butyrolactone. Importantly, early Mn exposure did not alter autoreceptor sensitivity when assessed in early adolescence or adulthood. The lack of Mn-induced effects was evident in both the dopamine synthesis and behavioral experiments. When considered together with past studies, it is clear that early Mn exposure alters the functioning of various dopaminergic presynaptic mechanisms, while dopamine autoreceptors remain unimpaired.European journal of pharmacology 02/2013; · 2.59 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: 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.Journal of Neurochemistry 02/2012; 120(3):385-95. · 3.97 Impact Factor