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    • The intricate roles and neural systems and

    2020-08-11

    The intricate roles and neural systems and mechanisms involved in the CRF1 and CRF2 mediation of spontaneous and stress-induced anxiety behavior remain to be defined. Of particular relevance are studies evaluating the behavioral actions of CRF1 and CRF2 receptors separately as well as together. For example, injecting rats with a dose of a CRF1 antagonist, DPC904 [61] in combination with a CRF2 antisense oligonucleotide resulted in lower levels of freezing than rats treated with only the CRF1 antagonist or the CRF2 antisense oligonucleotide [63]. Astressin, a CRF antagonist with high affinity for both CRF1 and CRF2 receptors and a potent inhibitor of apoptosis blocker of stress-induced ACTH secretion [82] may also provide information on the relative roles of CRF receptor subtypes, especially when used in combination with specific CRF receptor antagonists. For example, a study using astressin and anti-Svg-30 reported differential roles of CRF1 and CRF2 receptors in fear conditioning and anxiety [75].
    Introduction The maintenance of homeostasis and inhibitor of apoptosis to aversive situations requires an appropriate and coordinated set of physiological adjustments, including neuroendocrine and autonomic responses [1], [2], [3]. The autonomic nervous system provides the initial response to stress, which is characterized by blood pressure and heart rate (HR) increase, redistribution of blood flow (reduction to skin and viscera and increase for skeletal muscle), and modulation of baroreflex activity [1], [4], [5], [6]. The cutaneous vasoconstriction leads to a rapid fall in the skin temperature during stress [7], [8]. Physiological adjustments during emotional stress are mediated by activation of limbic structures through action of several neurochemical mechanisms [3], [9]. The bed nucleus of the stria terminalis (BNST) is a limbic structure localized in the rostral prosencephalon, which is a component of the “extended amygdala” (continuum formed by the BNST and centromedial amygdala) [10]. The BNST is activated during aversive threat [11] and has a direct influence in cardiovascular, neuroendocrine and behavioral responses to stress [12], [13]. Regarding the cardiovascular responses, previous findings from our group demonstrated that reversible inactivation of the BNST enhanced the HR increase evoked by acute restraint stress without affecting the blood pressure increase [14]. Conversely, BNST ablation attenuated the freezing behavior and the increase in blood pressure and HR induced by contextual fear conditioning [15], thus indicating that the role of the BNST in neurobiological mechanisms of emotional stress depends on the paradigm of stress. Nevertheless, although the above findings indicate a role of the BNST in the modulation of stress-evoked autonomic responses, the local neurochemical mechanisms involved in this control was not fully elucidated. The corticotropin-releasing factor (CRF) is a neuropeptide released in numerous limbic structures during aversive stimuli [9], which is involved in behavioral and physiological responses to emotional stress [16], [17], [18]. The CRF system in mammals is composed by the CRF and other three CRF-like peptides, denominated urocortin (Ucn) 1, Ucn2, and Ucn3 [16], [19]. The effects of CRF and Ucns are mediated by two receptors, denominated CRF1 and CRF2, and a CRF binding protein [16], [19]. The ligands present differences in the binding profile to CRF receptors. For instance, CRF has 10-fold higher affinity for CRF1 than for CRF2 receptors, while Ucn2 and Ucn3 bind with 100-fold higher affinities to the CRF2 receptor [19]. Ucn1 has similar affinities for both receptors [19]. High density of CRF-containing terminals, arising mainly from the central nucleus of the amygdala [20], [21], and moderate to dense Ucn1- and Ucn3-immunoreactive fibers [22], [23] were found within BNST. Also, populations of CRF- and Ucn3-containing neurons have been identified in the BNST [23], [24], [25]. Both CRF receptors are expressed within the BNST [26], [27]. A role of BNST CRF neurotransmission in behavioral response to aversive threats is well described [13]. However, the participation of this signaling mechanism in control of cardiovascular function is poorly understood [12]. Nijsen et al. [28] reported that BNST treatment with a nonselective CRF receptor antagonist enhanced the tachycardic response induced by contextual fear conditioning. However, the subtype of CRF receptor within the BNST involved in control of stress-evoked cardiovascular responses have never been investigated. Furthermore, although evidence that BNST differently modulate the responses to conditioned vs unconditioned aversive stimuli [14], [15], a possible role of local CRF signaling in the BNST in control of cardiovascular responses to innate stress is unknown. Therefore, in the present study we tested the hypothesis that CRF receptors in the BNST are involved in cardiovascular responses to acute restraint stress in rats. To this end, we investigated the effects of BNST treatment with either selective CRF1 or CRF2 receptor antagonists and agonists on the pattern of cardiovascular responses (arterial pressure and HR increase, and decrease in tail skin temperature) evoked by acute restraint stress.