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    • br Materials and methods br Results

    2020-07-29


    Materials and methods
    Results
    Discussion Substantial evidence shows that the negative reinforcement resulting from the aversive affective consequences of opiate withdrawal might play a crucial role in drug craving and relapse (Koob, 2009; Ungless et al., 2010). In the present study we have used the CPA paradigm for studying the involvement of CRF-CRF1R pathway in the negative affective component of opiate withdrawal as well as to investigate neural and molecular substrates underlying the aversive memory associated with CPA in morphine-withdrawn rats.
    Introduction Animal exposure to aversive stimuli induces fear- and anxiety-like behaviors (e.g., fight, flight, freezing and vocalization) as well as neuroendocrine (e.g., ACTH and corticosterone release) and autonomic (e.g., tachycardia, tachypnea, increased blood pressure and defecation) activations (Blanchard and Blanchard, 2003, Blanchard et al., 1993, Graeff, 1990). These defensive reactions are coordinated by various areas of the simvastin aversive system (Graeff, 1990). For instance, the midbrain periaqueductal gray, the hypothalamus, and the amygdaloid complex have been implicated in the modulation of behavioral, hormonal, and autonomic responses induced by dangerous and threatening situations (Bandler and Depaulis, 1991, Behbehani, 1995, Brandao et al., 2003, Carrive et al., 1997, Fanselow, 1991, Graeff et al., 1993, Lang et al., 1998, Lovick, 2000, Walker and Carrive, 2003). The amygdaloid complex has been widely investigated as an important modulator site of defensive responses, such as freezing, the startle reflex, antinociception, and heart rate alteration (Rosen and Schulkin, 1998), and its extensive connections to the bed nucleus of the stria terminalis (BNST) have raised substantial interest in the identification of the role of the BNST in the modulation of anxiety-related responses (Alheid, 2003, Davis, 1998, Heimer, 2003, Sahuque et al., 2006, Schulkin et al., 2005, Ventura-Silva et al., 2012). For instance, electrical stimulation of the BNST elicits behavioral and endocrine changes that are similar to those induced by environmental stressors (Casada and Dafny, 1991, Dunn, 1987). In contrast, pharmacological inactivation of the BNST decreases the expression of conditioned or unconditioned responses induced by aversive situations (Sahuque et al., 2006). 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 adenine 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 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).