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  • Previously published results on this topic are inconsistent

    2019-08-13

    Previously published results on this topic are inconsistent. Stressin1-A, a novel CRF1 receptor agonist, increased anxiety-like behavior in the social interaction and shock-probe tests [51]. Pharmacological blockade of CRF1 (NBI-30775) reversed both CRF-induced increases in startle and CRF-induced deficits in prepulse inhibition (PPI) [14]. CRF2 receptor blockade (ASV-30) attenuated high-dose, but not low-dose, CRF-induced increases in startle and reduced PPI [14]. Centrally administered ASV-30 reduced anxiety-like behavior in BALB/c mice in three models of anxiety: marble burying, open field, and elevated plus maze. ASV-30 did not change locomotor activity or the ACTH response to restraint stress [12]. In the literature, only two papers have demonstrated an anxiogenic-like effect of ASV-30 administration. When ASV-30 (400ng, 100pmol) was injected alone into the lateral intermediate septum, learning of a tone-dependent fear conditioning to context was enhanced. Such tonic control of learning was not observed when ASV-30 was injected into the dorsal hippocampus [52]. In the other study, a single injection of ASV-30 (400ng, i.c.v.) into adult, wild-type mice elicited anxious behavior in the elevated plus-maze test [46]. These data suggest a model in which respective CRF receptors modify the magnitude of defensive responses in fear-related behavior, with the CRF1 receptors triggering active defensive responses to stressors. The prevailing role of CRF1 receptors in this regard has been repeatedly shown [23], [53], [54], [55], [56], [57]. We do not have any unequivocal explanation concerning the discrepancy between our findings and some other authors’ findings regarding the behavioral effects of ASV-30, except for the fact that some of these experiments were performed on mice, and the differences may also depend on drug dose, Adriamycin HCl location, testing environment (e.g., conditioned versus unconditioned fear responses) or rat strain. For example, Takahashi et al. [11] found that ASV-30 produced a significant anxiolytic behavior in three animal model, including reduction in conditioned freezing, using male Sprague-Dawley rats. In the current study male Wistar rats have been used. Interestingly, we have recently observed the Sprague-Dawley rats exhibit much more aversive context-induced ultrasonic vocalization in comparison to Wistar rats (data in preparation), indicating that these strains of rats reveal different patterns of coping behavior. Intriguingly, CRF mRNA levels are elevated in the PVN in CRF1 receptor and double-mutant mice, and urocortin-3 and vasopressin mRNA levels are increased in CRF2 receptor and double-mutant mice [6], [47]. CRF2 receptor mutant mice showed elevated expression of CRF mRNA in the central amygdala [6]. These results indicate that both CRF1 and CRF2 receptors have critical roles in gene regulation and the maintenance of homeostasis in response to stress [6], [47]. From this study, it also appears that CRF2 receptor inactivation may contribute to an increase in the brain concentration of CRF, an agonist with a higher affinity for the CRF1 receptors [21], [22], [59], [60], [61]. In this way, the role of CRF1 receptors may be emphasized, and the behavioral and biochemical phenomena associated with the activation of these receptors are more strongly expressed. According to this hypothesis, the current results can be interpreted such that a selective blockade of CRF2 receptors by ASV-30 and AST-2B could facilitate the conduction of signals via CRF1 receptors, leading to an increase in anxiety-like responses. In other words, the fear-evoked release of CRF by the stimulation of functionally active CRF1 receptors could mediate the behavioral (anxiety-like) and biochemical (corticosterone level, c-Fos and CRF expression) effects of a conditioned fear. Consistent with this concept, we found a potent and significant potentiation by the CRF2 receptor antagonists of conditioned fear-induced increase in the density of CRF-immunoreactive complexes in the cortical and limbic brain structures, including the CeA. In keeping with this finding, it is well recognized that during periods of stress, CRF is released into the amygdala, and local CRF receptor activation has been postulated as a substrate for fear-induced alterations in the affective behavior [62], [63], [64].