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    • From the same perspective previous studies by

    2020-08-05

    From the same perspective, previous studies by Sajdyk and colleagues (Sajdyk et al., 1999) and Spiga and colleagues (Spiga et al., 2006) have shown that the administration of CRF or urocortin 1 (a selective agonist for CRF1 and CRF2 receptors but with a higher affinity for the CRF1 receptor) into the BLA produced an anxiogenic effect, as evaluated by a social interaction test in rats; this effect was reversed by the antagonism of CRF1 receptors. Again, intracerebroventricular or systemic injections of non-peptidic CRF1 antagonists (CP-154,526, antalarmin or DMP696) reduced defensive behavior in the elevated plus maze test and light/dark test [for review Bale and Vale (2004) and Carrasco and Van De Kar (2003)]. However, intra-septal, intracerebroventricular or systemic injections of CRF1 agonists attenuated defensive behavior (Radulovic et al., 1999). The study of Iemolo et al. (2013) strongly support the anxiolytic effect of CeA CRF1 blockage. They reported that a selective CRF1 antagonist (R121919) in CeA blocked the anxiogenic effect induced by palatable food withdrawn in a model for food intake in rats (Iemolo et al., 2013). Further, another finding showed that the administration of CRF2 receptor antagonists (antisauvagine-30) in the BLA was not effective in reducing fear responses in aversive conditioning (Hubbard et al., 2007). However, the administration of Astressin 2B into the medial amygdala decreased T-maze avoidance latencies, an anxiolytic-like effect (Alves et al., 2016). Together, these results support the involvement of CRF1 and CRF2 receptors in the modulation of fear and anxiety behaviors, but the ways in which these responses are modulated should be clarified. It is possible that the differences in behavioral effects are related to the independent neural circuits that mediate the distinct ethologic models correlated with defensive responses (Lowry and Moore, 2006). Regarding the mechanism of action of CRF, several studies have shown that low doses of CRF may preferentially activate CRF1 receptors in glutamatergic projection neurons, serotoninergic neurons or glutamatergic collaterals in the medial prefrontal KU14R (Vertes, 2004). Indeed, prosencephalic inactivation of CRF1 receptors (where glutamatergic neurons are highly expressed) reduced the emission of defensive responses (Refojo et al., 2011). It is important to note that both BLA and CeA have large numbers of glutamatergic neurons (McEwen and Wingfield, 2003), and glutamate receptors have been found to colocalize with CRF in the amygdala (Śmiałowska et al., 2002). In particular, previous studies have shown that BLA can modulate CeA efferents via direct projections to the medial subnucleus of the CeA (CeAm) as well through an indirect pathway that leads to negative feedback for the medial subdivision of the CeA via activation of GABAergic neurons in the lateral subdivision of the CeA (CeAl) (Haubensak et al., 2010, Tye et al., 2011). Although the mechanisms of the effects of this microcircuitry remain undefined, an increase in the release of CRF in CeAl has been shown to have the potential to enhance glutamatergic transmission (Silberman and Winder, 2013). In a recent review of Henckens and colleagues (Henckens et al., 2016), several convergent and contradicting findings as well as particularities and limitations were greatly discussed. Among the described particularities of CRF1 and CRF2 receptors that may explain our results, three of them should be here cited, to be concise: 1) all available agonists and antagonists have no absolute specificity for CRF receptors; 2) high ligand concentrations may act on both receptors; 3) signaling and downstream effects of CRF receptors are not fully known (Henckens et al., 2016). Nevetheless, it is important to cite that labeling and distribution of CRF receptors in the brain is still limited. Still, the knowledge about the site of action (pre- or pos-synaptic) and cell type expression are important questions to be addressed (Henckens et al., 2016). Noteworthy, the CRF system in stress- or emotion-related disorders is still a challenge and far to be simplistic. Although several studies have been conducted, the precise role of CRF receptors in emotional-related disorders is not well known. Moreover, due to the mechanistic complexity of CRF system, a broader role of CRF and its receptors should be considered.