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  • In this study we further investigated the involvement


    In this study, we further investigated the involvement of CRF1 and CRF2 receptors of the dPAG in the regulation of panic-related responses. For this, we used two animal models that associate escape behavior with panic attacks: the elevated T maze and the electrical stimulation of the dPAG (for a full description of these tests see Moreira et al., 2013, Zangrossi and Graeff, 2014). In the former test, besides escape, inhibitory avoidance acquisition is also measured, which has been associated in terms of psychopathology with generalized anxiety disorder (Blanchard et al., 2003, McNaughton and Corr, 2004).
    Materials and methods
    Results Fig. 1 depicts illustrative photomicrographs of injection sites into the dPAG, either in the dlPAG or the dmPAG. As can be seen in Table 1, in none of the studies performed with the elevated T-maze, did intra-dPAG injection of CRF or urocortin 2 interfere with locomotion in the open-field.
    Discussion The current finding is in agreement with results obtained by Carvalho-Netto et al. (2007) in the mouse defense test battery. In that test, intra-dPAG administration of CRF increased mice attempts to escape from an approaching predator (a hand held anesthetized rat), considered as a panicogenic-like effect. Interestingly, in these mice CRF also changed the receptor tyrosine kinase of defensive responses that have been associated with generalized anxiety disorder, such as avoidance of the predator and risk-assessment. Whereas the peptide increased the former reaction, it decreased the frequency and duration of risk-assessment, both indicating an anxiogenic effect. This finding is line with the observation that CRF in the dPAG facilitates open-arm avoidance in the elevated plus-maze (Borelli and Brandao, 2008, Martins et al., 1997, Miguel and Nunes-de-Souza, 2011) and contextual freezing expression (Borelli et al., 2013), both indices also associated with anxiety (Blanchard et al., 2005, Graeff and Zangrossi, 2002, McNaughton and Gray, 2000). It is noteworthy that results of experiment 1a revealed that, although CRF did not cause an overall effect on inhibitory avoidance acquisition, it significantly facilitated avoidance 2 learning at the highest dose tested (mean±SEM: saline=141.67±43.04, CRF 1μg=300±0.0, t=(13)=3.67; p<0.05), also indicating an anxiogenic effect. It deserves attention that at this dose all animals remained in the enclosed arm for 300s, the pre-determined cutoff time. Therefore, it is conceivable that the observation of a more expressive CRF anxiogenic response was limited by a ceiling effect. Evidence gathered in mice is also suggestive that type-1 receptors mediate CRF-evoked defensiveness in the dPAG. Using the elevated plus-maze, Miguel and Nunes-de-Souza (2011) reported that the peptide anxiogenic effect is blocked by NBI 27914, but not by antisauvagine, CRF1 and CRF2 receptor antagonists, respectively. This idea is strengthened by the current observation that intra-dPAG injection of urocortin 2, a CRF2 receptor agonist, causes anxiolysis and not anxiogenesis in the elevated T-maze inhibitory avoidance task (further details below). The finding that CRF facilitated escape performance both in the dmPAG and dlPAG contrasts with previous evidence showing a columnar differentiation on the effects of this peptide in the rat elevated plus-maze. More specifically, Borelli and Brandao (2008) showed that CRF caused anxiogenic effect after administration in the dmPAG, but not in the dlPAG or lateral columns of the PAG. The reason for this discrepancy is not clear. It may be related to the type of defensive behaviors in consideration in the two studies, a panic (escape)- and an anxiety (avoidance of the open arms)-associated reaction, which may be under a different control by these two PAG sub-areas. However, a more careful analysis of our data revealed that although CRF at the dose tested in experiment 1b (0.5μg) did not affect inhibitory avoidance acquisition either in the dmPAG or dlPAG, 1μg in experiment 1a was anxiogenic, with injection sites equally found within these two columns.