Methyl mercury enhances [3H]diazepam binding in different areas of the rat brain

doi:10.1016/0006-8993(81)90769-1

Brain Research

Volume 229, Issue 1, 14 December 1981, Pages 264-269

https://doi.org/10.1016/0006-8993(81)90769-1 Get rights and content

Summary

Three days after the acute oral administration of methyl mercury (MeHg), a 27–60% increase in the total number of binding sites for [³H]diazepam was seen in the retina and different areas of the rat brain, with no change, except in the retina, in the apparent dissociation constant for its ligand. In contrast, MeHg failed to change [³H]spiroperidol and [³H]GABA binding in the same areas. Moreover, MeHg decreased cyclic GMP content in the cerebellar cortex. The various possible mechanisms involved in the action of MeHg on benzodiazepine binding are discussed.

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Specific benzodiazepine receptors in the rat brain characterized by high-affinity³H-diazepam binding

Cited by (14)

Methylmercury induces an initial increase in GABA-evoked currents in Xenopus oocytes expressing α<inf>1</inf> and α<inf>6</inf> subunit-containing GABA<inf>A</inf> receptors
2017, NeuroToxicology
Citation Excerpt :
Then the question is how MeHg causes this initial increase or potentiation of IGABA. One possibility is that MeHg may directly interact with the GABA receptor complex and modulate the benzodiazepine or barbiturate modulation sites to cause this initial potentiation since MeHg increases the total number of benzodiazepine binding sites of GABAA receptors in the retina and other brain areas including the cerebellum (Corda et al., 1981; Concas et al., 1983; Komulainen et al., 1995; Fonfría et al., 2001). If this is the case, α6-containing receptors would be less responsive because the α1 subunit confers greater benzodiazepine sensitivity (Smith, 2001; Trincavelli et al., 2012).
Early onset effects of methylmercury (MeHg) on recombinant α₁β₂γ_2S or α₆β₂γ_2S subunit-containing GABA_A receptors were examined. These are two of the most prevalent receptor types found in cerebellum–a consistent target of MeHg-induced neurotoxicity. Heterologously expressed receptors were used in order to: (1) isolate receptor-mediated events from extraneous effects of MeHg due to stimulation of the receptor secondary to increased release of GABA seen with MeHg in neurons in situ and (2) limit the phenotypes of GABA_A receptors present at one time. Initial changes in I_GABA in Xenopus laevis oocytes expressing either α₁β₂γ_2S or α₆β₂γ_2S receptors were compared during continuous bath application of MeHg. A time-dependent increase in I_GABA mediated by both receptor subtypes occurred following the first 25–30 min of MeHg (5 μM) exposure. In α₆β₂γ_2S containing receptors, the MeHg-induced increase in I_GABA was less pronounced compared to that mediated by α₁β₂γ_2S containing receptors, although the pattern of effects was generally similar. Washing with MeHg-free solution reversed the increase in current amplitude. Application of bicuculline at the time of peak potentiation of I_GABA rapidly and completely reversed the MeHg-induced currents. Therefore these MeHg-increased inward currents are mediated specifically by the two subtypes of GABA_A receptors and appear to entail direct actions of MeHg on the receptor. However bicuculline did not affect stimulation by MeHg of oocyte endogenous Cl⁻ -mediated current, which presumably results from increased [Ca²⁺]_i. Thus, MeHg initially potentiates I_GABA in oocytes expressing either α₁β₂γ_2S or α₆β₂γ_2S receptors prior to its more defined later effects, suggesting that MeHg may initially interact directly with GABA_A receptors in a reversible manner to cause this potentiation.
In vitro and whole animal evidence that methylmercury disrupts GABAergic systems in discrete brain regions in captive mink
2010, Comparative Biochemistry and Physiology - C Toxicology and Pharmacology
The effects of mercury (Hg) on key components of the GABAergic system were evaluated in discrete brain regions of captive juvenile male American mink (Neovison vison) using in vitro and in vivo (whole animal) experimental approaches. In vitro studies on cortical brain tissues revealed that inorganic Hg (HgCl₂; IC50 = 0.5 ± 0.2 µM) and methyl Hg (MeHgCl; IC50 = 1.6 ± 0.2 µM) inhibited glutamic acid decarboxylase (GAD; EC 4.1.1.15) activity. There were no Hg-related effects on [³H]-muscimol binding to GABA(A) receptors (IC50s > 100 µM). HgCl₂ (IC50 = 0.8 ± 0.3 µM) but not MeHgCl (IC50 > 100 µM) inhibited GABA-transaminase (GABA-T; EC 2.6.1.19) activity. In a whole animal study, neurochemical indicators of GABAergic function were measured in brain regions (occipital cortex, cerebellum, brain stem, and basal ganglia) of captive mink fed relevant levels of MeHgCl (0 to 2 µg/g feed, ppm) daily for 89 d. No effects on GAD activity were measured. Concentration-dependent decreases in [³H]-muscimol binding to GABA(A) receptors and GABA-T activity were found in several brain regions, with reductions as great as 94% (for GABA(A) receptor levels) and 71% (for GABA-T activity) measured in the brain stem and basal ganglia. These results show that chronic exposure to environmentally relevant levels of MeHg disrupts GABAergic signaling. Given that GABA is the main inhibitory neurotransmitter in the mammalian nervous system, prolonged disruptions of its function may underlie the sub-clinical impacts of MeHg at relevant levels to animal health.
The importance of glutamate, glycine, and γ-aminobutyric acid transport and regulation in manganese, mercury and lead neurotoxicity
2005, Toxicology and Applied Pharmacology
Historically, amino acids were studied in the context of their importance in protein synthesis. In the 1950s, the focus of research shifted as amino acids were recognized as putative neurotransmitters. Today, many amino acids are considered important neurochemicals. Although many amino acids play a role in neurotransmission, glutamate (Glu), glycine (Gly), and γ-aminobutyric acid (GABA) are among the more prevalent and better understood. Glu, the major excitatory neurotransmitter, and Gly and GABA, the major inhibitory neurotransmitters, in the central nervous system, are known to be tightly regulated. Prolonged exposure to environmental toxicants, such as manganese (Mn), mercury (Hg), or lead (Pb), however, can lead to dysregulation of these neurochemicals and subsequent neurotoxicity. While the ability of these metals to disrupt the regulation of Glu, Gly and GABA have been studied, few articles have examined the collective role of these amino acids in the respective metal's mechanism of toxicity. For each of the neurotransmitters above, we will provide a brief synopsis of their regulatory function, including the importance of transport and re-uptake in maintaining their optimal function. Additionally, the review will address the hypothesis that aberrant homeostasis of any of these amino acids, or a combination of the three, plays a role in the neurotoxicity of Mn, Hg, or Pb.
Toxicokinetic interactions and survival of Hyalella azteca exposed to binary mixtures of chlorpyrifos, dieldrin, and methyl mercury
2001, Aquatic Toxicology
Chemical mixture interactions of chlorpyrifos, dieldrin, and methyl mercury were evaluated in Hyalella azteca. Survival of adult and juvenile organisms was evaluated following exposure to individual chemicals and in binary combinations. Binary interactions of the model chemicals on survival of adult and juvenile H. azteca were evaluated by concentration–response curve analysis as additive, synergistic, antagonistic, or independent. Chlorpyrifos and methyl mercury interacted additively, while dieldrin interacted independently with both chlorpyrifos and methyl mercury. Toxicodynamic interactions were evaluated by measuring accumulation and elimination of each model toxicant in the presence of a second toxicant. Chlorpyrifos significantly increased the amount of methyl mercury accumulated in the first 12 h of exposure. Dieldrin did not interact with chlorpyrifos or methyl mercury in the accumulation or elimination experiments. Accumulation of chlorpyrifos was not observed. Results of the current investigation demonstrate that chlorpyrifos and methyl mercury interact additively, which would otherwise be predicted to act independently.
Interactions of neurotoxicants with neurotransmitter systems
1988, Toxicology
Many neurotoxic compounds have been shown to interfere with neurotransmission both in vitro and following acute and chronic administration. Various parameters of neurotransmission can be directly affected by neurotoxicants; these include the enzyme(s) synthesizing a neurotransmitter, the release and uptake processes, the enzyme(s) which metabolize the neurotransmitter, the receptors, and post-synaptic events associated with receptor activation. Some neurotoxicants can interfere with neurotransmission indirectly, by interacting for example with energy metabolism, sodium channels or ATPases. Furthermore, measured alterations of any parameter of neurotransmission can be the result of neuronal death, due to a cytotoxic effect of the neurotoxicants. Chemicals which have been shown to alter neurotransmission include solvents (e.g. carbon disulfide), metals and organometals (e.g. lead, mercury, trimethltin) and pesticides (e.g. organophosphates, pyrethroids, organochlorines, formamidines). An example of the various alterations in neurotransmitter parameters, which can occur following acute or chronic administration, is represented by the organophosphates. Organophosphorus insecticides owe their acute toxicity to inhibition of acetylcholinesterase and accumulation of acetylcholine at cholinergic receptors. Chronic exposure to these compounds results in the development of tolerance to their toxicity which is associated with a decrease in the density of muscarinic and nicotinic receptors in both the central and peripheral nervous system. Other examples of the interactions of neurotoxicants with neurotransmitters are also described.
In vivo modulation of muscarine receptors in rat brain by acute lead intoxication
1984, Toxicology
In our experiments on acutely lead exposed rats we observed a marked increase (a 2-fold or 3-fold increase with 30 mg/kg or 60 mg/kg lead acetate, respectively) in [³H]quinuclidinyl benzilate ([³H]QNB) specific binding to muscarine receptors from striatum and cortex, without any change in receptor affinity. Muscarine receptor level was maximal 2 h after intoxication, but the effect of lead on [³H]QNB binding was completely reversible in 24 h, without any lead redistribution to other brain areas being observed during this time period. Modulation of muscarine receptors in rat brain during in vivo acute intoxication might be involved in some of the observed neurotoxic effects of lead, resulting of an action on cholinergic neurotransmission. The various possible mechanisms of the lead effect on [³H]QNB binding are discussed.

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Methyl mercury enhances [3H]diazepam binding in different areas of the rat brain

Summary

Brain Research

Brain Research

Environ. Res.

Neurosci. Lett.

Environ. Res.

Brain Research

Biochem. Pharmacol.

J. biol. Chem.

Neuropharmacology

Brain Research

Mechanisms by which diazepam muscimol and other drugs change the content of cGMP in cerebellar cortex

Specific benzodiazepine receptors in the rat brain characterized by high-affinity3H-diazepam binding

Methyl mercury enhances [³H]diazepam binding in different areas of the rat brain

Specific benzodiazepine receptors in the rat brain characterized by high-affinity³H-diazepam binding