A Synaptic Mechanism Underlying the Behavioral Abnormalities Induced by Manganese Intoxication

Calabresi, Paolo; Ammassari–Teule, Martine; Gubellini, Paolo; Sancesario, Giuseppe; Morello, Maria; Centonze, Diego; Marfia, Girolama Alessandra; Saulle, Emilia; Passino, Enrica; Picconi, Barbara; Bernardi, Giorgio

doi:10.1006/nbdi.2000.0379

Cited by 72 publications

(58 citation statements)

References 35 publications

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“…In particular, the effect of manganese on motor function has been reliably reproduced in different animals and experimental paradigms; this effect is apparent across a wide range of doses, different routes of administration and chemical species of manganese (Calabresi et al, 2001;Dodd et al, 2005;Mohammad and Faris, 2006;Nam and Kim, 2008;Newland and Weiss, 1992;Normandin et al, 2004). Manganese treatment typically results in decreased motor activity or disturbances in motor coordination, although a manganese-induced hyperactivity has also been reported (Calabresi et al, 2001;Eriksson et al, 1987). The effects are usually reversible, dose-dependent and often remain long after the end of manganese administration.…”

Section: Manganese-induced Motor Dysfunctionmentioning

confidence: 97%

“…Various symptoms of manganese toxicity are routinely tested in animals (Burton and Guilarte, 2009;Calabresi et al, 2001;Gwiazda et al, 2007;Newland, 1999;Olanow et al, 1996;Shukakidze et al, 2003). In particular, the effect of manganese on motor function has been reliably reproduced in different animals and experimental paradigms; this effect is apparent across a wide range of doses, different routes of administration and chemical species of manganese (Calabresi et al, 2001;Dodd et al, 2005;Mohammad and Faris, 2006;Nam and Kim, 2008;Newland and Weiss, 1992;Normandin et al, 2004). Manganese treatment typically results in decreased motor activity or disturbances in motor coordination, although a manganese-induced hyperactivity has also been reported (Calabresi et al, 2001;Eriksson et al, 1987).…”

Section: Manganese-induced Motor Dysfunctionmentioning

confidence: 99%

“…Although the mechanisms underlying manganese neurotoxicity remain unclear, experimental evidence exists that manganese may affect dopaminergic and cholinergic neuromodulatory systems, which may lead to various cognitive and neurological disorders including motor dysfunction (Calabresi et al, 2001;Eriksson et al, 1987;Nam and Kim, 2008;Newland and Weiss, 1992;Olanow et al, 1996). Taking this into account, a successful application of MEMRI technique for longitudinal studies, particularly involving behaving animals, critically depends on the manganese administration regimen that does not or minimally compromise homeostatic capacity, while achieving MRI-detectable cumulative concentration of Mn 2+ in the brain.…”

Section: Manganese-induced Motor Dysfunctionmentioning

confidence: 99%

“…In general, various forms of locomotor activity are used as an indicator of manganese toxicity (Calabresi et al, 2001;Gwiazda et al, 2007;Nam and Kim, 2008;Newland and Weiss, 1992). In the present study, we demonstrated a significant decrease in rat running activity after a single systemic injection of all tested doses of MnCl 2 (16-80 mg/kg) using the voluntary wheel running model.…”

Section: Voluntary Running As An Indicator Of Manganese-induced Toxicitymentioning

confidence: 99%

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Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies

et al. 2010

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Magnetic resonance imaging (MRI) is widely used in basic and clinical research to map the structural and functional organization of the brain. An important need of MR research is for contrast agents that improve soft-tissue contrast, enable visualization of neuronal tracks, and enhance the capacity of MRI to provide functional information at different temporal scales. Unchelated manganese can be such an agent, and manganese-enhanced MRI (MEMRI) can potentially be an excellent technique for localization of brain activity (for review see Silva et al., 2004). Yet, the toxicity of manganese presents a major limitation for employing MEMRI in behavioral paradigms. We have tested systematically the voluntary wheel running behavior of rats after systemic application of MnCl 2 in a dose range of 16-80 mg/kg, which is commonly used in MEMRI studies. The results show a robust dose-dependent decrease in motor performance, which was accompanied by weight loss and decrease in food intake. The adverse effects lasted for up to 7 postinjection days. The lowest dose of MnCl 2 (16 mg/kg) produced minimal adverse effects, but was not sufficient for functional mapping. We have therefore evaluated an alternative method of manganese delivery via osmotic pumps, which provide a continuous and slow release of manganese. In contrast to a single systemic injection, the pump method did not produce any adverse locomotor effects, while achieving a cumulative concentration of manganese (80 mg/kg) sufficient for functional mapping. Thus, MEMRI with such an optimized manganese delivery that avoids toxic effects can be safely applied for longitudinal studies in behaving animals.

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Section: Manganese-induced Motor Dysfunctionmentioning

confidence: 97%

Section: Manganese-induced Motor Dysfunctionmentioning

confidence: 99%

Section: Manganese-induced Motor Dysfunctionmentioning

confidence: 99%

Section: Voluntary Running As An Indicator Of Manganese-induced Toxicitymentioning

confidence: 99%

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Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies

et al. 2010

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“…(Golub et al, 2005). In adult rats, unlearned locomotor responding is often disrupted by perturbations of the nigrostriatal and mesocorticolimbic dopamine systems, therefore it is surprising that Mn has been reported to increase (Nachtman et al, 1986;Calabresi et al, 2001), decrease (Ingersoll et al, 1995;Talavera et al, 1999), or have no effect (Dorman et al, 2000;Reichel et al, 2006) on spontaneous locomotor activity. Interestingly, Mn-exposed rats show reduced locomotor responsiveness when challenged with cocaine or amphetamine (indirect dopamine agonists), suggesting that subtle motoric deficits can be unmasked by pharmacological challenge Reichel et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Postnatal manganese exposure alters dopamine transporter function in adult rats: Potential impact on nonassociative and associative processes

McDougall¹,

Reichel²,

Farley³

et al. 2008

Neuroscience

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In the present study, we examined whether exposing rats to a high-dose regimen of manganese chloride (Mn) during the postnatal period would depress presynaptic dopamine functioning and alter nonassociative and associative behaviors. To this end, rats were given oral supplements of Mn (750 μg/day) on postnatal days (PD) 1-21. On PD 90, dopamine transporter (DAT) immunoreactivity and [ 3 H]dopamine uptake were assayed in the striatum and nucleus accumbens, while in vivo microdialysis was used to measure dopamine efflux in the same brain regions. The effects of postnatal Mn exposure on nigrostriatal functioning were evaluated by assessing rotorod performance and amphetamine-induced stereotypy in adulthood. In terms of associative processes, both cocaineinduced conditioned place preference (CPP) and sucrose-reinforced operant responding were examined. Results showed that postnatal Mn exposure caused persistent declines in DAT protein expression and [ 3 H]dopamine uptake in the striatum and nucleus accumbens, as well as long-term reductions in striatal dopamine efflux. Rotorod performance did not differ according to exposure condition, however Mn-exposed rats did exhibit substantially more amphetamine-induced stereotypy than vehicle controls. Mn exposure did not alter performance on any aspect of the CPP task (preference, extinction, or reinstatement testing), nor did Mn affect progressive ratio responding (a measure of motivation). Interestingly, acquisition of a fixed ratio task was impaired in Mn-exposed rats, suggesting a deficit in procedural learning. In sum, these results indicate that postnatal Mn exposure causes persistent declines in various indices of presynaptic dopaminergic functioning. Mninduced alterations in striatal functioning may have long-term impact on associative and nonassociative behavior.

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Nmr spectroscopic analysis of regional brain energy metabolism in manganese neurotoxicity

Zwingmann¹,

Leibfritz²,

Hazell³

2007

Glia

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A central question in manganese neurotoxicity concerns the focal neuronal damage in the globus pallidus. In the present study, we investigated specific pathways of [1-(13)C]glucose as well as of [2-(13)C]acetate in this brain region and the frontal cortex following 4-day manganese treatment by high-resolution NMR spectroscopy. Following administration of 50 mg/kg/day manganese, glutamine concentration in the globus pallidus was decreased to 67% of control values but increased in frontal cortex by 56%. Manganese treatment also caused pronounced changes in glutamine-glutamate-GABA interconversion in which region-selective differences were observed in the isotopomer pattern of GABA compared with that of glutamine when including the astrocyte-specific substrate [2-(13)C]acetate. In particular, decreased (13)C-labeled glutamine, synthesized from [1-(13)C]glucose, paralleled accumulation of (13)C-labeled GABA in globus pallidus but not in frontal cortex. On the other hand, increased synthesis of glutamine from [2-(13)C]acetate showed that GABA accumulation was not due to increased synthesis from astrocytic glutamine. Furthermore, treatment with manganese resulted in a selective decrease in N-acetyl-aspartate in the globus pallidus. These data illustrate the potential importance of alterations in neuronal metabolic function. In particular, neuronal metabolic derangements and regional differences in the ability of astrocytes to fulfill their contribution to the glutamine-glutamate-GABA cycle during the early phase of manganese neurotoxicity may be crucial in determining the severity of cellular injury.

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A Synaptic Mechanism Underlying the Behavioral Abnormalities Induced by Manganese Intoxication

Cited by 72 publications

References 35 publications

Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies

Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies

Postnatal manganese exposure alters dopamine transporter function in adult rats: Potential impact on nonassociative and associative processes

Nmr spectroscopic analysis of regional brain energy metabolism in manganese neurotoxicity

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