N-acetylcysteine prevents stress-induced anxiety behavior in zebrafish Ricieri Mocelin a,1 , Ana P. Herrmann b,1 , Matheus Marcon a , Cassiano L. Rambo c , Aline Rohden a , Fernanda Bevilaqua a , Murilo Sander de Abreu d , Leila Zanatta a , Elaine Elisabetsky b , Leonardo J.G. Barcellos d,e , Diogo R. Lara c,g , Angelo L. Piato f,g, ⁎ a Programa de Pós-Graduação em Ciências Ambientais, Universidade Comunitária da Região de Chapecó, Av. Senador Attílio Fontana, 591E, 89809-000 Chapecó, SC, Brazil b Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, 90035-000 Porto Alegre, RS, Brazil c Laboratório de Neuroquímica e Psicofarmacologia, Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Av. Ipiranga, 6681, 90619-900 Porto Alegre, RS, Brazil d Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, Campus Universitário, Camobi, 97105-900 Santa Maria, RS, Brazil e Programa de Pós-Graduação em Bioexperimentação, Universidade de Passo Fundo, BR 285, 99052-900 Passo Fundo, RS, Brazil f Laboratório de Psicofarmacologia e Comportamento, Programa de Pós-Graduação em Farmacologia e Terapêutica, Universidade Federal do Rio Grande do Sul, Av. Sarmento Leite 500/202, 90050-170 Porto Alegre, RS, Brazil g Zebrafish Neuroscience Research Consortium (ZNRC), USA abstract article info Article history: Received 20 December 2014 Received in revised form 28 May 2015 Accepted 4 August 2015 Available online 7 August 2015 Keywords: N-acetylcysteine Anxiety Stress Zebrafish Despite the recent advances in understanding the pathophysiology of anxiety disorders, the pharmacological treatments currently available are limited in efficacy and induce serious side effects. A possible strategy to achieve clinical benefits is drug repurposing, i.e., discovery of novel applications for old drugs, bringing new treat- ment options to the market and to the patients who need them. N-acetylcysteine (NAC), a commonly used mu- colytic and paracetamol antidote, has emerged as a promising molecule for the treatment of several neuropsychiatric disorders. The mechanism of action of this drug is complex, and involves modulation of antiox- idant, inflammatory, neurotrophic and glutamate pathways. Here we evaluated the effects of NAC on behavioral parameters relevant to anxiety in zebrafish. NAC did not alter behavioral parameters in the novel tank test, prevented the anxiety-like behaviors induced by an acute stressor (net chasing), and increased the time zebrafish spent in the lit side in the light/dark test. These data may indicate that NAC presents an anti-stress effect, with the potential to prevent stress-induced psychiatric disorders such as anxiety and depression. The considerable ho- mology between mammalian and zebrafish genomes invests the current data with translational validity for the further clinical trials needed to substantiate the use of NAC in anxiety disorders. © 2015 Elsevier Inc. All rights reserved. 1. Introduction Despite the recent advances in understanding the pathophysiology of psychiatric disorders, pharmaceutical industries are increasingly abandoning drug development programs in this field. Exorbitant finan- cial losses consequent to high failure rates in early stage clinical trials are the most likely explanation for this current situation, which includes arrested development of agents once considered as promising novel treatments (Insel, 2012). A possible strategy to bypass this drug pipeline drain is the repurposing of available drugs, which reduces uncertainty regarding safety and pharmacokinetic issues and allows a faster track to achieve clinical benefits (Ashburn and Thor, 2004; Insel et al., 2013). N-acetylcysteine (NAC) – a commonly used mucolytic and paraceta- mol antidote – has emerged as a promising molecule for the treatment of several neuropsychiatric disorders, such as bipolar disorder, schizo- phrenia and drug addiction (Dean et al., 2011a; Berk et al., 2013). The myriad of positive clinical data is related to the multi-target profile of NAC, which modulates antioxidant, inflammatory, neurotrophic and glutamate pathways (Dean et al., 2011b). Specifically for glutamate, NAC activates the astrocytic cystine–glutamate antiporters, leading to glutamate release, stimulation of extra-synaptic metabotropic gluta- mate receptors (mGluRs) and decreased neurotransmitter synaptic re- lease (Baker et al., 2002; Moran et al., 2005). When an organism is subjected to stressful situations, the innate stress response activates several biologic systems in order to elicit coping strategies and restore homeostasis (Chrousos and Gold, 1992; McEwen, 2007; Gold, 2015). There are, however, maladaptive responses to stressors, which are closely linked to the development of anxiety disorders and depression (Sapolsky, 2000). Although no approved treatment for stress and anxiety targets the glutamatergic system, there is consistent experimental evidence implicating Pharmacology, Biochemistry and Behavior 139 (2015) 121–126 ⁎ Corresponding author at: Programa de Pós-Graduação em Farmacologia e Terapêutica, ICBS, Universidade Federal do Rio Grande do Sul, Av. Sarmento Leite 500/ 305, 90050-170 Porto Alegre, RS, Brazil. E-mail address: angelopiato@ufrgs.br (A.L. Piato). 1 These authors contributed equally for this article. http://dx.doi.org/10.1016/j.pbb.2015.08.006 0091-3057/© 2015 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh