Fear like behaviors are produced by intracerebroventricular

Fear-like behaviors are produced by intracerebroventricular CRF administration (Meloni et al., 2006, Radulovic et al., 1999), as well its administration into specific BGP-15 areas such as the amygdala (Daniels et al., 2004, Donatti and Leite-Panissi, 2011), the periaqueductal gray matter (Martins et al., 1997), the hippocampus (Radulovic et al., 1999), and the lateral septum (Bakshi et al., 2002). In this way, while antagonist CRF1 receptors have pronounced effects in normalizing stress-induced anxiety when CRF is released, CRF2 receptors appear be involved in the expression of both stress-induced anxiety and spontaneous anxiety behavior (Takahashi, 2001). Moreover, although preclinical data using CRF1 receptor antagonists in experimental animal models were unclear concerning their antidepressant activity (Nielsen, 2006), this receptor is considered to be possible target for the treatment of psychiatric diseases (Arborelius et al., 1999, Heinrichs et al., 1997, Reul and Holsboer, 2002). Additionally, previous study has shown that the activation of neurons that express CRF2 in the lateral septum promotes persistent anxious behavior, as evaluated by the light-dark box test, the open field test and the novel object test in mice (Anthony et al., 2014). Many studies have used paradigms based on animal models to understand human emotional behavior because it appears to be correlated with fear- and anxiety-related defensive patterns in non-human mammals (Blanchard et al., 2001). In this case, defensive reactions are used to study the neural substrate of the modulation of innate fear and anxiety responses (Canteras, 2003). Defensive reactions are triggered based on prey-predator distance (Ratner, 1967) and on the degree of threat posed by the situation (Blanchard and Blanchard, 1988). Therefore, when a predator or other dangerous stimulus is very close to the prey and physical contact is possible, behavioral responses such as fight or flight are exhibited. However, when physical contact is prolonged and there is no chance to escape, the prey’s last attempt to survive is the tonic immobility (TI) response, or “death feigning” (Klemm, 2001). The tonic immobility (TI) response is an innate and reversible defensive response characterized by profound physical inactivity and relative lack of responsivity to environmental stimuli (Klemm, 2001, Ratner, 1967). This behavior is shown during situations of extreme, inescapable threat (Gallup, 1977) and is observed in many species of invertebrate and vertebrate animals (Klemm, 2001, Ratner, 1967) including humans (Volchan et al., 2011). In fact, previous studies have suggested that tonic immobility can predict the severity of posttraumatic stress disorder (PTSD) symptoms (Fiszman et al., 2008, Lima et al., 2010, Rocha-Rego et al., 2009). During the TI response, neurovegetative and behavioral alterations are observed, including vocalizations, intermittent eye closure, muscular stiffness, parkinsonism-like tremors (Jones, 1986), and alterations in neural activity (Rusinova and Davydov, 2010) as well as changes in heart rate, breathing (Giannico et al., 2014), and body temperature (Eddy and Gallup, 1990). The neurophysiological events that occur while TI is exhibited have been observed in aversive emotional states and resemble innate fear (Nash et al., 1976). Recently, Alves and colleagues (Alves et al., 2014) have demonstrated a positive correlation between heart rate changes after viewing trauma-related pictures and tonic immobility scores in individuals exposed to a traumatic event. This innate fear response can be induced in the laboratory by a manual inversion and restriction of animal movements; tactile and proprioceptive sensations are essential to trigger TI behavior (Gallup, 1977, Klemm, 2001). Regarding the neural substrates involved in TI modulation, previous studies have shown that distinct structures of the central nervous system, such as the periaqueductal gray matter (Vieira et al., 2011), hypothalamus (De Oliveira et al., 1997), and amygdaloid complex (Donatti and Leite-Panissi, 2011, Donatti and Leite-Panissi, 2009, Leite-Panissi et al., 2006, Leite-Panissi et al., 2003, Leite-Panissi and Menescal-de-Oliveira, 2002), are intimately related to the modulation of this behavior. In this context, distinct neurotransmitter systems, including CRF receptors in the central (CeA) or basolateral (BLA) nucleus of the amygdala, can alter TI duration. This effect is possibly due to the modulation of fear and anxiety but is not due to increased spontaneous motor activity, which may affect TI behavior nonspecifically (Donatti and Leite-Panissi, 2011, Donatti and Leite-Panissi, 2009, Leite-Panissi et al., 2006, Leite-Panissi et al., 2003, Leite-Panissi and Menescal-de-Oliveira, 2002). In particular, Donatti and Leite-Panissi (Donatti and Leite-Panissi, 2011) showed that the activation of CRF receptors in the BLA or CeA increased the TI response, whereas treatment with a non-selective CRF antagonist, alpha-helical-CRF9-41, decreased this innate fear response. So, these data support the role of the amygdaloid CRF system in the control of emotional responses; however, further experiments are required to understand the interplay between CRF receptors and the TI response to provide support for the development of new drugs to treat emotional disorders in humans.