Developmental exposure to methylmercury alters behavioral sensitivity to D-amphetamine and pentobarbital in adult rats.

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Abstract

Female rats were exposed to 0, 0.5, or 6.4 ppm methylmercury in their drinking water before mating, and throughout gestation and lactation. When the female offspring were 4-6 months old, they were trained to respond under a multiple differential reinforcement of high rate (DRH) 9:4-- Extinction schedule of reinforcement. No differences among exposure groups were apparent in steady-state behavior. Drug challenges were conducted with multiple doses of D-amphetamine, scopolamine, pentobarbital, haloperidol, and dizocilpine, drugs selected for their different pharmacological effects. The ED(50) values for amphetamine's reinforcement rate-reducing effects for the control, 0.5-, and 6.4-ppm groups were 3.1, 1.9, and 0.9 mg amphetamine/kg body weight, respectively, demonstrating an increased sensitivity to D-amphetamine in methylmercury-exposed rats. Rats in the 6.4-ppm group also demonstrated a relative insensitivity to pentobarbital. Further, these exposed rats exhibited an inverted U-shaped dose-effect curve under the pentobarbital dose-effect determination, while controls showed only a declining curve. Exposed rats did not respond differentially to haloperidol, scopolamine, or dizocilpine, suggesting specificity. The present data suggest an involvement of catecholaminergic and GABAergic activity in methylmercury's neurotoxicity.

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Methylmercury developmental neurotoxicity: A comparison of effects in humans and animals

Thomas Burbacher, Patricia M Rodier, Bernard Weiss (1990)

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Polychlorinated biphenyls and methylmercury act synergistically to reduce rat brain dopamine content in vitro.

J Bemis, R Seegal (1999)

Consumption of contaminated Great Lakes fish by pregnant women is associated with decreased birth weight and deficits in cognitive function in their infants and children. These fish contain many known and suspected anthropogenic neurotoxicants, making it difficult to determine which contaminant(s) are responsible for the observed deficits. We have undertaken a series of experiments to determine the relevant toxicants by comparing the neurotoxic effects of two of these contaminants--polychlorinated biphenyls (PCBs) and methylmercury (MeHg)--both of which are recognized neurotoxicants. Striatal punches obtained from adult rat brain were exposed to PCBs only, MeHg only, or the two in combination, and tissue and media concentrations of dopamine (DA) and its metabolites were determined by high performance liquid chromatography. Exposure to PCBs only reduced tissue DA and elevated media DA in a dose-dependent fashion. Exposure to MeHg only did not significantly affect either measure. However, when striatal punches were simultaneously exposed to PCBs and MeHg, there were significantly greater decreases in tissue DA concentrations and elevations in media DA than those caused by PCBs only, in the absence of changes in media lactate dehydrogenase concentrations. Elevations in both tissue and media 3, 4-dihydroxyphenylacetic acid concentrations were also observed. We suggest that the significant interactions between these two toxicants may be due to a common site of action (i.e., toxicant-induced increases in intracellular calcium and changes in second messenger systems) that influences DA function. The synergism between these contaminants suggests that future revisions of fish-consumption guidelines should consider contaminant interactions. Images Figure 1 Figure 2 Figure 3 Figure 4

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Interactions of methylmercury with rat primary astrocyte cultures: inhibition of rubidium and glutamate uptake and induction of swelling.

M. Aschner, N.B. Eberle, K. Miller … (1990)

The ability of astrocytes to sequester MeHg may indicate an astrocyte-mediated role in MeHg's neurotoxicity. Hence, studies were undertaken to assess the effects of MeHg on metabolic functions in cultured astrocytes. MeHg (10(-5) M) significantly inhibited the initial rate (5 min) of uptake of 86RbCl, used as a tracer for K+. 86RbCl uptake was also sensitive to the omission of medium Na+. MeHg (10(-5) M) also markedly inhibited the initial rate of uptake (1 min) of the Na(+)-dependent uptake of [3H]L-glutamate. A second neurotoxin, MnCl2 (0-5 x 10(-4) M), did not alter [3H]glutamate or 86RbCl uptake. MeHg, but not MnCl2, also stimulated the release of intracellular 86Rb+ in a dose-dependent fashion. This effect could be prevented by the administration of MeHg as the glutathione conjugate. These observations support the hypothesis that the astrocyte plasma membrane is an important target for MeHg's toxic effect and specifically that small concentrations of this organometal inhibit the ability of astrocytes to maintain a transmembrane K+ gradient. This would be expected to compromise the ability of astrocytes to control extracellular K+ either by spatial buffering or active uptake, resulting in cellular swelling. We therefore studied volume changes in astrocytes using uptake of [14C]3-O-methyl-D-glucose, in attached cells in response to exposure to MeHg. Exposure to MeHg (0-5 x 10(-4) M) caused a marked increase in the cell volume that was proportional to concentrations of MeHg.