Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates

Guilarte, Tomás R.; Chen, Ming Kai; McGlothan, Jennifer L.; Verina, Tatyana; Wong, Dean F.; Zhou, Yun; Alexander, Mohab; Rohde, Charles A.; Syversen, Tore; Decamp, Emmanuel; Koser, Amy Jo; Fritz, Stephanie A.; Gonczi, Heather; Anderson, David W.; Schneider, Jay S.

doi:10.1016/j.expneurol.2006.06.015

Cited by 176 publications

(196 citation statements)

References 51 publications

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“…For example, exposing monkeys to Mn reduces striatal dopamine content and alters dopamine release characteristics (Bird et al, 1984;Guilarte et al, 2006). In rats, infusion of Mn during microdialysis reduces K + -stimulated dopamine efflux in the striatum (Vidal et al, 2005), while chronic Mn exposure causes longterm reductions in striatal dopamine levels (Gianutosos and Murray, 1982;Komura and Sakamoto, 1992;Ingersoll et al, 1995;Tran et al, 2002a,b;Aschner et al, 2005).…”

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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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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“…Studies in non-human primates chronically exposed to Mn 2+ indicate that while the globus pallidus accumulates the highest concentration of Mn 2+ , other brain regions also exhibit significant elevations in Mn 2+ concentrations (Dorman et al, 2006;Guilarte et al, 2006). For example, Dorman et al, (2006) showed that at any of the Mn 2+ exposure levels administered to monkeys via inhalation, there were significant elevations of Mn 2+ not only in basal ganglia structures but also in the frontal cortex, olfactory cortex, cerebellum and white matter.…”

Section: Introductionmentioning

confidence: 99%

Manganese inhibits NMDA receptor channel function: Implications to psychiatric and cognitive effects

Guilarte

Chen

2007

NeuroToxicology

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Humans exposed to excess levels of manganese (Mn 2+ ) express psychiatric problems and deficits in attention and learning and memory. However, there is a paucity of knowledge on molecular mechanisms by which Mn 2+ produces such effects. We now report that Mn 2+ is a potent inhibitor of [ 3 H]-MK-801 binding to the NMDA receptor channel in rat neuronal membrane preparations. The inhibition of [ 3 H]-MK-801 to the NMDA receptor channel by Mn 2+ was activity-dependent since Mn 2+ was a more potent inhibitor in the presence of the NMDA receptor co-agonists glutamate and glycine (K i = 35.9 ± 3.1 μM) than in their absence (K i = 157.1 ± 6.5 μM). We also show that Mn 2+ is a NMDA receptor channel blocker since its inhibition of [ 3 H]-MK-801 binding to the NMDA receptor channel is competitive in nature. That is, Mn 2+ significantly increased the affinity constant (K d ) with no significant effect on the maximal number of [ 3 H]-MK-801 binding sites (B max ). Under stimulating conditions, Mn 2+ was equipotent in inhibiting [ 3 H]-MK-801 binding to NMDA receptors expressed in neuronal membrane preparations from different brain regions. However, under basal, non-stimulated conditions, Mn 2+ was more potent in inhibiting NMDA receptors in the cerebellum than other brain regions. We have previously shown that chronic Mn 2+ exposure in non-human primates increases Cu 2+ , but not zinc or iron concentrations in the basal ganglia (Guilarte et al., Experimental Neurology 202: 381-390, 2006). Therefore, we also tested the inhibitory effects of Cu 2+ on [ 3 H]-MK-801 binding to the NMDA receptor channel. The data shows that Cu 2+ in the presence of glutamate and glycine is a more potent inhibitor of the NMDA receptor than Mn 2+ . Our findings suggest that the inhibitory effect of Mn 2+ and/or Cu 2+ on the NMDA receptor may produce a deficit in glutamatergic transmission in the brain of individuals exposed to excess levels of Mn 2+ and produce neurological dysfunction.

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“…In one study (Newland & Weiss, 1992), monkeys were exposed to manganese, a metal that accumulates in the basal ganglia and that produces (at high doses) dystonic postures, gait disturbances, and tremor (Guilarte et al, 2006;Mena, Horiuchi, Burke, & Cotzias, 1969;Newland, 1999). Before exposure, the monkeys were trained to produce an effortful, rowing-type action through a 10-centimeter displacement against a spring that resisted movement with a force approximating the monkeys' body weight.…”

Section: Motor Deficitsmentioning

confidence: 99%

Environmental health and behavior analysis: Contributions and interactions.

Newland¹

2013

APA Handbook of Behavior Analysis, Vol. 2: Translating Principles Into Practice.

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The heightened public awareness that environmental contaminants can act on the nervous system and have effects that appear in behavior presents a major challenge to behavioral scientists in all areas. They are being asked to conduct both hazard assessment (are there neurobehavioral effects of some chemical at any dose?) and risk assessment (what is the risk to a population at a specific level of exposure?) for behavioral effects that are not always well understood. The heavy metal lead provides an excellent example. Concern over lead poisoning lies in claims that it lowers scores on IQ tests, retards academic performance, and results in disruptive and even criminal behavior. The problems posed are daunting: How easy is it to detect a 5-point drop in scores on IQ tests? Can scientists predict these effects from experimental models using laboratory animals? Can they identify behavioral and neural mechanisms that account for these effects? What economic costs are incurred if the average IQ drops a few points, and how does this cost compare with that of reducing lead in the environment?These concerns are reflected in policymaking. Federal legislation and regulation of toxic substances specifically include behavior, including schedule-controlled operant behavior, as a regulatory endpoint (Tilson, 1990). The inclusion of nervous system damage in general, and its behavioral manifestations in particular, represents a sea change in public concern over unintended exposure to chemicals. Where cancer has been (and still is) a significant concern, the recognition that adverse behavioral effects follow certain types of chemical exposure is increasing. These effects carry over into a large number of domains. Environmental contaminants, even at very low exposure levels, contribute to disorders across the life span, including developmental disabilities and the hastening of age-related impairments. Behavioral scientists' understanding of how this happens not only has public policy implications but can also inform them about the behavior and neurobiology surrounding these disorders.

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Nigrostriatal dopamine system dysfunction and subtle motor deficits in manganese-exposed non-human primates

Cited by 176 publications

References 51 publications

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

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

Manganese inhibits NMDA receptor channel function: Implications to psychiatric and cognitive effects

Environmental health and behavior analysis: Contributions and interactions.

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