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  • These contrasting results observed with intra BNST

    2019-11-22

    These contrasting results observed with intra-BNST combined injections of NOC-9 and CP 376395 on freezing (in the novel arena) versus anxiety-related behavior (in the EPM) suggest that CRF neurotransmission within this forebrain limbic site could be mainly involved in the modulation of more subtle anxiety-like responses. This assumption is supported by previous studies showing that CRF injection into various Sulindac sulfone mg areas induces an anxiogenic effect devoid of motor explosive reaction, such as jumping and running (Miguel et al., 2014, Miguel and Nunes-de-Souza, 2011, Sahuque et al., 2006). In other words, this peptide might be modulating less intense and aversive behavioral responses (e.g., avoidance to the open arms of the EPM) rather than freezing response. In contrast to what we observed with CP 376395, intra-BNST injection of AP-7 alone attenuated anxiety-like responses in mice exposed to the EPM (Fig. 4). At the highest dose used (0.20nmol), this NMDA receptor antagonist increased %OE and %OT, suggesting an anxiolytic-like effect. These results are suggestive that glutamate plays a tonic role in the modulation of anxiety (assessed in the mouse EPM) by acting at NMDA receptors located within the BNST. Interestingly, when injected before NOC-9, 0.05nmol of AP-7, a dose devoid of intrinsic effects on anxiety (see Fig. 4), produced a similar effect to that observed with the blockade of CRF1 receptors (Fig. 6A/B). In other words, intra-BNST AP-7 (0.05nmol) did not block NOC-9 induced freezing (Fig. 6A), however, it attenuated the main anxiogenic-like effects provoked by this NO donor in mice exposed to the EPM (Fig. 6B). In line with the above assumption that NO would lead to CRF release into the BNST, these results also suggest that the increase in NO production would stimulate glutamate release in this forebrain structure. Finally, we have hypothesized that glutamate, which is usually related to explosive motor reactions modulated by NMDA receptors (Aguiar et al., 2006, Miguel and Nunes-de-Souza, 2006, Molchanov and Guimaraes, 1999), could play a role in the freezing response induced by NOC-9 injected into the BNST. Surprisingly, despite attenuating the anxiogenic-like effect of NOC-9, AP-7 failed to change the freezing behavior induced by the NO donor, suggesting a dissociative mediation of glutamate in these NO-induced defensive responses. It is noteworthy, however, that we have used only a single dose of AP-7 to investigate the role of NMDA receptors in the modulation of the freezing induced by NOC-9. Further studies employing higher doses of AP-7 need to be conducted to clarify the role of the NMDA receptors located within the BNST in the modulation of this defense behavior.
    Introduction Corticotropin-releasing factor (CRF) is a 41-amino acid neuropeptide and mediates its actions through two Gs-coupled G protein-coupled receptor subtypes, CRF1 and CRF2.1, 2 CRF is considered to be the main regulator of the hypothalamus–pituitary–adrenocortical (HPA) axis via CRF1 receptors.3, 4 After exposure to stress, secretion of CRF increases in the neurons of the paraventricular nucleus of the hypothalamus and stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland.5, 6 In healthy individuals not suffering from life-threatening events, a negative feedback system against the activation of the HPA-axis is operating; in contrast, the system collapses in patients with stress-related disorders. Moreover, CRF plays an important role in the brain as a neurotransmitter that mediates stress-related behaviors.4, 7 In our previous study, we designed unique benzazole derivatives with a single-atom linker between the core and the pendant phenyl group as novel CRF1 receptor antagonists. Initial structure-activity-relationship (SAR) studies revealed that lead compound 1 shown in Figure 1 demonstrated potent in vitro CRF1 receptor binding activity with an IC50 value of 12nM and ex vivo CRF binding inhibitory activity in the brain after oral administration in mice. Compound 1 has a di-alkylamino moiety located in a para orientation of the hydrogen-bonding acceptor (HBA) of the N-methylbenzimidazole core to fit into a large lipophilic pocket of the CRF1 receptor. We were also interested in placing an alkyl-arylamino group at the same position of the benzimidazole core and whether it would bind more effectively in the lipophilic pocket. In addition, previous SAR studies indicated that a normal propyl group can be replaced with an isopropyl group and the branched alkyl group can be expected to effectively occupy the large three-dimensional pocket compared with a linear group. Therefore, compounds in which these alkyl groups were replaced with an aryl group and a branched alkyl group were designed and examined.