The effects of methylmercury on motor activity are sex- and age-dependent, and modulated by genetic deletion of adenosine receptors and caffeine administration

Björklund, Olga; Kahlström, Johan; Salmi, Peter; Ögren, Sven Ove; Vahter, Marie; Chen, Jiang‐Fan; Fredholm, Bertil B.; Daré, Elisabetta

doi:10.1016/j.tox.2007.08.092

Cited by 35 publications

(26 citation statements)

References 76 publications

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“…4). This increase in activity counts was approximately equal in magnitude to that seen in A 1 R KO mice and reported elsewhere (5). Mice that had received oral caffeine (Fig.…”

Section: Measurement Of the Concentrations Of Caffeine And Its Activesupporting

confidence: 84%

Mice heterozygous for both A₁ and A_2A adenosine receptor genes show similarities to mice given long-term caffeine

Yang¹,

Björklund²,

Lindström-Törnqvist³

et al. 2009

Journal of Applied Physiology

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I, Fredholm BB. Mice heterozygous for both A1 and A2A adenosine receptor genes show similarities to mice given long-term caffeine. J Appl Physiol 106: 631-639, 2009. First published November 26, 2008 doi:10.1152/japplphysiol.90971.2008.-Caffeine is believed to exert its stimulant effects by blocking A2A and A1 adenosine receptors (A2AR and A1R). Although a genetic knockout of A2AR eliminates effects of caffeine, the phenotype of the knockout animal does not resemble that of caffeine treatment. In this study we explored the possibility that a mere reduction of the number of A1Rs and A2ARs, achieved by deleting one of the two copies of the A1R and A2AR genes, would mimic some aspects of long-term caffeine ingestion. The A1R and A2AR double heterozygous (A1R-A2AR dHz) mice indeed had approximately one-half the number of A1R and A2AR, and there were little compensatory changes in A2B or A3 adenosine receptor (A2BR or A3R) expression. The ability of a stable adenosine analog to activate receptors was shifted to the right by caffeine and in A1R-A2AR dHz tissue. Caffeine (0.3 g/l in drinking water for 7-10 days) and A1R-A2AR dHz genotype increased locomotor activity (LA) and decreased heart rate without significantly influencing body temperature. The acute stimulatory effect of a single injection of caffeine was reduced in A1R-A2AR dHz mice and in mice treated long term with oral caffeine. Thus at least some aspects of long-term caffeine use can be mimicked by genetic manipulation of the A1R and A2AR. knockout; locomotor activity; tolerance; receptor binding; lipolysis CAFFEINE IS THE MOST WIDELY consumed psychoactive drug (15). It is generally believed that most of its actions in habitually consumed doses can be explained by its being an antagonist of adenosine receptors (12, 15). Since competitive antagonists are active if the receptors are occupied by an agonist, only adenosine receptors that are activated by endogenous adenosine under physiological conditions are likely targets for the effects of caffeine. Therefore, the focus has been on adenosine A 1 and A 2A receptors (A 1 R and A 2A R) (15), because these receptors where abundantly expressed are activated by endogenous adenosine levels. Indeed, it has been shown that some of the effects of caffeine are eliminated by knocking out the A 2A R (10, 20). However, the phenotype of the A 2A R knockout (KO) mouse is different from that of a caffeine-treated mouse. In doses commonly consumed by humans, caffeine (and its breakdown products) will bind to 25-50% of the A 1 R and A 2A R. Such blockade if continued for a long time may have functional consequences similar to a reduction in receptor number. Our group (2, 22) has previously shown that mice with only a single copy of the adenosine A 1 or A 2A gene have approximately one-half the number of receptors. Therefore, we hypothesize that mice that have a reduced number (rather than a complete elimination) of both A 1 Rs and A 2A Rs may show features of mice that are treated for a long time with caffeine, and subsequent...

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“…4). This increase in activity counts was approximately equal in magnitude to that seen in A 1 R KO mice and reported elsewhere (5). Mice that had received oral caffeine (Fig.…”

Section: Measurement Of the Concentrations Of Caffeine And Its Activesupporting

confidence: 84%

Mice heterozygous for both A₁ and A_2A adenosine receptor genes show similarities to mice given long-term caffeine

Yang¹,

Björklund²,

Lindström-Törnqvist³

et al. 2009

Journal of Applied Physiology

Self Cite

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“…In fact, children exposed to MeHg may exhibit decreased IQ, impaired movements, visuospatial perception, and speech, a medical phenomenon known as fetal Minamata disease (FMD) [45–47]. The effects of developmental exposure to MeHg on animal behavior include, among others, reduced motor activity [52] and a decrease in memory [53–55] and learning [56]. Studies modeling in utero human exposures in postnatal rat pups, show that MeHg can alter the expression of many developmental regulators and genes involved in small GTPase signaling pathways regulating cell growth and proliferation [57].…”

Section: Introductionmentioning

confidence: 99%

Methylmercury and brain development: A review of recent literature

Santos

Hort

Culbreth

et al. 2016

Journal of Trace Elements in Medicine and Biology

144

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Methylmercury (MeHg) is a potent environmental pollutant, which elicits significant toxicity in humans. The central nervous system CNS) is the primary target of toxicity, and is particularly vulnerable during development. Maternal exposure to MeHg via consumption of fish and seafood can have irreversible effects on the neurobehavioral development of children, even in the absence of symptoms in the mother. It is well documented that developmental MeHg exposure may lead to neurological alterations, including cognitive and motor dysfunction. The neurotoxic effects of MeHg on the developing brain have been extensively studied. The mechanism of toxicity, however, is not fully understood. No single process can explain the multitude of effects observed in MeHg-induced neurotoxicity. This review summarizes the most current knowledge on the effects of MeHg during nervous system development considering both, in vitro and in vivo experimental models. Considerable attention was directed towards the role of glutamate and calcium dyshomeostasis, mitochondrial dysfunction, as well as the effects of MeHg on cytoskeletal components/regulators.

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“…In vivo rodent models developmentally exposed to MeHg exhibited neurobehavioral (e.g., motor activity, startle response, learning/memory ability, or activity related with one's motivation) and/or physiological (e.g., brain gene expression, enzymatic activity, or neuronal cell damage) changes [124,126,[156][157][158][159][160][161][162][163][164][165]. Interestingly, the effects of developmental MeHg exposure may be different depending on sex or age of test animals at the time of DNT evaluation.…”

Section: Methylmercurymentioning

confidence: 99%

Zebrafish as a Model for Developmental Neurotoxicity Assessment: The Application of the Zebrafish in Defining the Effects of Arsenic, Methylmercury, or Lead on Early Neurodevelopment

Lee

Freeman

2014

Toxics

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Developmental exposure to neurotoxic chemicals presents significant health concerns because of the vulnerability of the developing central nervous system (CNS) and the immature brain barrier. To date, a short list of chemicals including some metals have been identified as known developmental neurotoxicants; however, there are still numerous chemicals that remain to be evaluated for their potential developmental neurotoxicity (DNT). To facilitate evaluation of chemicals for DNT, the zebrafish vertebrate model system has emerged as a promising tool. The zebrafish possesses a number of strengths as a test species in DNT studies including an abundance of embryos developing ex utero presenting ease in chemical dosing and microscopic assessment at all early developmental stages. Additionally, rapid neurodevelopment via conserved molecular pathways supports the likelihood of recapitulating neurotoxic effects observed in other vertebrates. In this review, we describe the biological relevance of zebrafish as a complementary model for assessment of DNT. We then focus on a metalloid and two metals that are known developmental neurotoxicants (arsenic, methylmercury, and lead). We summarize studies in humans and traditional vertebrate models and then detail studies defining the toxicity of these substances using the zebrafish to support application of this model system in DNT studies.

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The effects of methylmercury on motor activity are sex- and age-dependent, and modulated by genetic deletion of adenosine receptors and caffeine administration

Cited by 35 publications

References 76 publications

Mice heterozygous for both A₁ and A_2A adenosine receptor genes show similarities to mice given long-term caffeine

Mice heterozygous for both A₁ and A_2A adenosine receptor genes show similarities to mice given long-term caffeine

Methylmercury and brain development: A review of recent literature

Zebrafish as a Model for Developmental Neurotoxicity Assessment: The Application of the Zebrafish in Defining the Effects of Arsenic, Methylmercury, or Lead on Early Neurodevelopment

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