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  • Although many neurotransmitters e g catecholamines serotonin


    Although many neurotransmitters (e.g., catecholamines, serotonin, and excitatory/inhibitory amino acids) have been implicated in the modulation of anxiety-like responses (Carobrez et al., 2001, Molchanov and Guimaraes, 2002, Vianna et al., 2001), the so-called atypical neurotransmitters, endocannabinoids and nitric oxide (NO), as well as the peptide corticotrophin-releasing factor (CRF) have more recently gained attention as important candidates in the modulation of emotional states (Esplugues, 2002, Fogaca et al., 2012, Guimaraes et al., 2005, Howlett et al., 2002, Piomelli, 2003). NO is a diffusible gas produced by the nitric oxide synthase (NOS) enzyme, through conversion of l-arginine to l-citrulline, using nicotinamide D609 receptor dinucleotide phosphate (NADPH) and Ca as co-factors (Lohse et al., 1998, Mayer et al., 1991). Among the three main NOS isoforms, neuronal NOS (nNOS) is the constitutive form expressed in neurons (de Oliveira et al., 2000). Proaversive effects (e.g., fight and flight reactions) have been demonstrated after injection of NO donors [e.g., SIN-1 (3-morpholino-sylnomine hydrochloride) and NOC-9 (6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine)] into the periaqueductal gray (PAG) in rats and mice (Guimaraes et al., 2005, Miguel et al., 2012). However, while SIN-1 produces peroxynitrite, a substance that can provoke cytotoxic effects and cause other NO-independent cellular effects (Del Carlo and Loeser, 2002, Morot Gaudry-Talarmain et al., 1997), NOC-9, which is relatively stable at alkaline pH (>10.0), releases NO at physiological pH (7.4) without producing peroxynitrite (Ambalavanan et al., 1999, Del Carlo and Loeser, 2002, Seccia et al., 1996). Conversely, intra-PAG injection of nNOS inhibitors, guanylate cyclase inhibitors, and an NO scavenger D609 receptor provokes anxiolytic-like effects in rats exposed to the elevated plus-maze (EPM) (Guimaraes et al., 1994). In mice, intra-PAG injection of a highly selective and potent nNOS inhibitor, NΩ-propyl-l-arginine (NPLA), attenuates defensive behavior in the rat exposure test, a prey–predator interaction test (Carvalho-Netto et al., 2009) and blocks NMDA (N-methyl-d-aspartate)-induced anxiogenic-like effects in the EPM (Nunes-de-Souza et al., 2010). The anxiogenic effects of NO may be related to its interference with the release of neurotransmitters, such as acetylcholine, GABA, dopamine, serotonin, glutamate, and CRF in distinct brain areas related to the defensive response (de Oliveira et al., 2000, Moreira and Guimaraes, 2004, Moreira et al., 2004). For instance, Guimaraes et al. (2005) have demonstrated that glutamate receptor antagonists are able to attenuate the proaversive effect of NO donors in the PAG. We have also observed that blocking the CRF type 1 receptor (CRF1) within the mouse PAG attenuates the proaversive effects produced by local injection of NOC-9, a NO donor (Miguel et al., 2012). Very few studies have investigated the role of nitrergic transmission within the BNST in the context of aversive reactions. Previous studies have demonstrated that the nitrergic neurons located within the BNST are activated by aversive stimuli in rats (Beijamini and Guimaraes, 2006, Guimaraes et al., 2005). Moreover, glutamatergic (McElligott and Winder, 2008) and CRFergic neurons have been identified in the BNST (Cummings et al., 1983, Ju et al., 1989, Morin et al., 1999, Sakanaka et al., 1987, Swanson et al., 1983). However, while the anxiogenic-like effects of NO seem to be modulated by NMDA-glutamate and CRF1 receptors within other limbic brain structures (e.g., PAG, inferior colliculus) (de Araujo Moreira et al., 2003, Guimaraes et al., 2005, Miguel et al., 2012, Miguel and Nunes-de-Souza, 2008), it remains unclear whether these interactions play a role within the BNST on the modulation of anxiety-like responses. Taken together, these lines of evidence suggest that the facilitation of nitrergic neurotransmission in the BNST may induce anxiogenic-like behavior, which may in turn be modulated by CRF and NMDA-glutamate receptors. In this paper, we investigate the effects of intra-BNST injection of NOC-9, a NO donor, on the behavior of mice exposed to a novel arena and to the EPM. The effects of intra-BNST injection of CRF1 or NMDA receptor antagonists, n-(1-ethylpropyl)-3,6-dimethyl-2-(2,4,6-trimethylphenoxy)-4-pyridinamine hydrochloride (CP376395) and 2-amino-7-phosphonoheptanoic acid (AP-7), on the behavioral effects induced by local injection of NOC-9 are also investigated.