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  • Regarding the mechanism of action of CRF several studies hav

    2020-01-11

    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 cortex (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 L-745,870 trihydrochloride 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.
    Conclusion The results of the present study suggest that blockade of CRF1 and CRF2 receptors in the BLA and CeA reduces the duration of TI behavior, probably due to decreased fear and/or anxiety. It is possible that this effect of specific CRF receptor antagonists can occur by reduction of endogenous activation of CRF induced by TI. Further, it was not due to altered spontaneous motor activity, which may non-specifically affect TI behavior. Our findings support the hypothesis that increased activation of CRF receptors, CRF1 and CRF2, in the BLA and CeA is responsible for anxiogenic and fearful responses.
    Author contributions
    Conflicts of interest
    Acknowledgements The authors would like to thank Patrícia Adriana Basile for her technical assistance. This work was supported by CAPES/PROEX, FAPESP (2010/10936-5). R.L. Spinieli is the recipient of a Master’s degree scholarship from CAPES and C.R.A. Leite-Panissi received research grants from the CNPq (# 307383/2012-1).
    Introduction Major depression is a complex and recurrent lifelong illness, characterized by repeated periods of exacerbation and remission. Despite the number of treatments available (which focus mainly on addressing modulation of monoamine neurotransmitters), significant unmet needs remain in terms of efficacy, onset of effect, and tolerability. Currently-available antidepressant drugs take 6–8weeks to exert their effect, and ∼30% of patients are non-responders; moreover drug-induced side effects reduce patient compliance. Extensive attempts have been made to identify the relevant biological targets contributing to the main pathophysiological mechanisms of anxiety and depressive disorders with the aim of getting more efficacious and safer treatments with rapid relief of symptoms.