Conclusion

In the above-mentioned studies, we assumed that the increased uptake of Hg° into CNS could affect sleep: (i) due to the further increase of extracellular concentrations of glutamate, which leads to the induction of excitotoxic effects that can have an impact on disbalance of cholinergic, glutaminergic and dopaminergic activity and other neuronal activity which otherwise regulate non-REM sleep, REM sleep and awakening , and (ii) due to the decreased night-time melatonin level, which also seems to be involved in day-night glutamate regulation and sleep-wake regulating actions by the activation of melatonin receptors in SCN and in the peripheral organ cells regulating other circadian 24-hour rhythms.

In vitro and in vivo studies have shown that due to the increased production of free radicals as well as blocked sodium and calcium channels, Hg inhibits the uptake of some neurotransmitters, especially glutamate, into astrocytes, which increases their extracellular concentration, thus increasing the sensitivity of neighbouring neurons for stimulating excitotoxic effects (Aschner et al., 2007; Castoldi et al., 2001). The increased production of the neurotransmitter nitrogen oxide (NO) mediated by Hg (Ikeda et al., 1999) is also indirectly included in the excitotoxic effects of glutamate (Dawson et al., 1991). Hg° thus additionally increases the physiological level of extracellular glutamate and its glutaminergic activity during REM sleep and awakening. It is not expected that Hg++-mediated glutamate accumulation in extracellular space can decline during non-REM-SWA sleep through intracellular-astrocyte uptake by glutamate/asparate transporters and its degradation into glutamine, whose capacity is satisfactory in physiological conditions (Dash et al., 2009), but probably not in Hg++-enhanced glutaminergic activity. It seems that the decrease of melatonin mediated by interaction with Hg++ can also decrease the uptake of glutamate in astrocytes, which additionally contributes to pathological glutaminergic overactivity at increased Hg++ concentrations in CNS.

Given the results of some animal studies (Lena et al., 2005; Morari et al., 1998) and human data (Burbure et al., 2006; Entezari-Taher et al., 1999; Lucchini et al., 2003; Missale et al., 1998), it is expected that Hg++ enhances the dopaminergic effect in CNS, otherwise associated with cortical hyperexcitability and changes in the control of locomotor function. The impaired subcortical dopaminergic system, which may cause disinhibition at motor cortex level, could be associated with periodic contractile movements of the legs in the sleep (Entezari-Taher et al., 1999; Ondo et al., 2000; Rijsman et al., 2005; Ziemann et al., 1996) observed in miners during increased Hg° absorption and intoxication. We can not completely exclude the potential additive effect of sub-clinical peripheral neuropathy observed in miners, which can trigger and modify the appearance of periodic leg contractile movements in sleep.

Melatonin is decreased in the night-time, either because of decreased synthesis under the influence of Hg-mediated, increased NO production, which in SCN operates similarly to a light signal (Ding et al., 1994; Ikeda et al., 1999), or by lowering its precursor tryptophan through its increased metabolizing, and because of its consumption in interaction with free radicals (McNally et al., 2008; Sener et al., 2003; Tan et al., 2000). A lower melatonin level is, at the same time, associated with the increased production of NO and its free radicals, peroxyntrites, which also increase the excitotoxic effects of glutamate (Acuna-Castroviejo et al., 1995; Leon et al., 1998). However, it has been established in many studies that melatonin plays a role in mediation between the circardian pacemaker and sleep-wake behaviour, and may have soporiphic properties and induce sedation, as well as the decreased nocturnal melatonin level labilised circadian rhythm function (Rodenbeck & Hajak, 2001; Stone et al., 2000; Turek & Gillette, 2004).

Increased extracellular glutamate and its decreased uptake in astrocytes (Dash et al., 2009) could hypothetically lead to longer REM periods and more frequent awakening associated with more frequent dreaming during increased Hg° absorption or intoxication. Hypothetically, persistent glutaminergic activity can also disrupt delta wave sleep, which could be associated with the sleep terrors observed in intoxicated miners. Further animal studies would be very helpful in elucidating the potential effects of Hg on the uptake of extracellular glutamate into astrocytes during the non-REM sleep, which could be relevant for sleep disorders observed in states of increased Hg° absorption or intoxication.

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