Possible role of serotoninergic system in the neurobehavioral impairment induced by acute methylmercury exposure in zebrafish (Danio rerio) Caio Maximino a, b, ⁎, Juliana Araujo a, b , Luana Ketlen Reis Leão a , Alan Barroso Araújo Grisolia a , Karen Renata Matos Oliveira a , Monica Gomes Lima a , Evander de Jesus Oliveira Batista a, c , Maria Elena Crespo-López d , Amauri Gouveia Jr. e , Anderson Manoel Herculano a, b, ⁎ a Laboratório de Neuroendocrinologia, Instituto de Ciências Biológicas, Universidade Federal do Pará, Brazil b Zebrafish Neuroscience Research Consortium, Brazil c Laboratório de Protozoologia, Núcleo de Medicina Tropical, Universidade Federal do Pará, Brazil d Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal do Pará, Brazil e Laboratório de Neurociências e Comportamento, Núcleo de Teoria e Pesquisa do Comportamento, Universidade Federal do Pará, Brazil abstract article info Article history: Received 31 March 2011 Received in revised form 8 August 2011 Accepted 9 August 2011 Available online 25 August 2011 Keywords: Zebrafish Oxidative stress Anxiety Methylmercury Serotonin Adult zebrafish were treated acutely with methylmercury (1.0 or 5.0 μgg -1 , i.p.) and, 24 h after treatment, were tested in two behavioral models of anxiety, the novel tank and the light/dark preference tests. At the smaller dose, methylmercury produced a marked anxiogenic profile in both tests, while the greater dose produced hyperlocomotion in the novel tank test. These effects were accompanied by a decrease in extracellular levels of serotonin, and an increase in extracellular levels of tryptamine-4,5-dione, a partially oxidized metabolite of serotonin. A marked increase in the formation of malondialdehyde, a marker of oxidative stress, accompanied these parameters. It is suggested that methylmercury-induced oxidative stress produced mitochondrial dysfunction and originated tryptamine-4,5-dione, which could have further inhibited tryptophan hydroxylase. These results underscore the importance of assessing acute, low-level neurobehavioral effects of methylmercury. © 2011 Elsevier Inc. All rights reserved. 1. Introduction Methylmercury (MeHg) is a pervasive environmental contaminant that causes marked neurobehavioral effects, including memory deficits and anxiety-like effects (Bakir et al., 1980; Carratù et al., 2006; Liang et al., 2009; Maia et al., 2010). This organic mercury species bioaccumulates in the food chain, and its effects are cumulative and dose-dependent (Elhassani, 1982; Mahaffey, 2000). While chronic, high-level poisoning events such as those described in Japan (Harada, 1995) and Iraq (Bakir et al., 1973) certainly require attention, descriptions of early effects of MeHg poisoning are few. The characterization of these effects can contribute to the development of markers for early deficits caused by methylmercury poisoning (Mahaffey, 2000). In the central nervous system, the main neurochemical effect of methylmercury poisoning seems to be excitotoxicity-mediated oxida- tive stress (Aschner et al., 2007; Nascimento et al., 2008; Yee and Choi, 1996). In vivo exposure to MeHg causes its accumulation inside mitochondria followed by a series of biochemical changes, including reduced cellular respiration and decreases in the activity of mitochon- drial enzymes such as cytochrome C oxidase, superoxide dismutase, monoamine oxidase (MAO) and succinate dehydrogenase (Bernstssen et al., 2003; Beyrouty et al., 2006; Cambier et al., 2009; Chakrabarti et al., 1998; Dreiem and Seegal, 2007; Kirubagaran and Joy, 1990; Levesque and Atchison, 1992; Mori et al., 2007; Ram and Sathyanesan, 1985). The disruption of the electron transport chain in the mitochondria and the dysfunction of energetic metabolism lead to the formation of reactive oxygen species (ROS) (Ali et al., 1992; Aschner et al., 2007; Carvan et al., 2001; Kusik et al., 2008; Nascimento et al., 2008; Sarafian, 1999; Sarafian et al., 1994; Shanker et al., 2002). One of the main cellular defenses against these ROS, glutathione, is also affected by MeHg. This toxicant inhibits cysteine uptake in astrocytes and the activity of glutathione peroxidase, thereby depleting intracellular glutathione levels (Aschner et al., 2007; Franco et al., 2009; Shanker et al., 2001, 2005). MeHg also inhibits glutamate uptake in glial cells, producing a glutamatergic accumulation in the synaptic cleft and, ultimately, resulting in further increases in ROS formation and excitotoxicity (Aschner et al., 2007; Nascimento et al., 2008). In addition to the effects of MeHg on glutamate-mediated excitotoxicity and ROS formation, alterations were also observed in Neurotoxicology and Teratology 33 (2011) 727–734 ⁎ Corresponding authors at: Laboratório de Neuroendocrinologia, Instituto de Ciências Biológicas, Universidade Federal do Pará. R. Augusto Corrêa, 01, 66075-110, Belém/PA, Brazil. Tel.: + 5591 3201 7742. E-mail addresses: caio@ufpa.br (C. Maximino), herculano@ufpa.br (A.M. Herculano). 0892-0362/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ntt.2011.08.006 Contents lists available at SciVerse ScienceDirect Neurotoxicology and Teratology journal homepage: www.elsevier.com/locate/neutera