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  • Conversely to the reduction in

    2019-07-08

    Conversely to the reduction in restraint-evoked HR increase following the blockade of CRF receptors, Nijsen et al. [28] demonstrated that BNST treatment with a nonselective CRF WDR5 0103 of antagonist enhanced the tachycardia evoked by contextual fear conditioning. Taken together, these results indicate that CRF neurotransmission in the BNST display distinct roles in control of cardiovascular adjustments during conditioned vs unconditioned aversive stimuli. This finding is in line with previous data demonstrating that either nonselective inhibition of BNST neurotransmission caused by local treatment with CoCl2 [14], [15] or BNST treatment with cannabidiol (a component of Cannabis sativa) [44], [45] caused opposite effects in cardiovascular responses to contextual fear conditioning and restraint stress. Both the sympathetic and parasympathetic nervous systems are directly responsible for cardiovascular adjustments during stress. For instance, stress-evoked tachycardia is abolished by blockade of cardiac sympathetic activity while inhibition of cardiac parasympathetic activity increases this response [46], [47], thus suggesting a coactivation of cardiac sympathetic and parasympathetic activity during aversive threats. The pressor response is mediated by a vasoconstriction in splanchnic, renal and cutaneous vascular territories [5], [6] through activation of α1-adrenoreceptors in vascular smooth muscle [47]. The vasoconstriction reduces the blood flow in cutaneous beds [6], which causes a fall in skin temperature [7], [8]. It has been reported that intracerebroventricular administration of CRF evokes a sympathetic-mediated increase in blood pressure and HR [48], [49]. Also, the reduction in stress-evoked tachycardia caused by intracerebroventricular administration of a nonselective CRF receptor antagonist was abolished in animals systemically treated with a blocker of cardiac parasympathetic activity [34], whereas intracerebroventricular injection of CRF reduced the restraint-evoked activation of dorsal motor nucleus of the vagus [50], indicating that CRF control of HR during aversive threat may also be mediated by an inhibition of cardiac parasympathetic activity. Direct projections from the BNST reach medullary structures involved with autonomic control, including the nucleus of the solitary tract, nucleus ambiguus, and ventrolateral regions [51], [52]. Thus, activation of CRF receptors within the BNST can modulate the cardiovascular activity during restraint through a facilitation of inhibitory inputs to medullary parasympathetic neurons and/or activation of facilitatory pathways to premotor sympathetic neurons. Results obtained with the CRF receptor antagonists provided evidence that physiological release of CRF and CRF-related peptides within the BNST during restraint modulates the tachycardia through activation of local CRF1 receptors while CRF2 receptors mediates the tail skin temperature responses. Moreover, both receptors control the increase in arterial pressure. Nevertheless, BNST treatment with CRF and Ucn3 affected both blood pressure, HR and skin temperature responses. Therefore, although the specificity of CRF1 and CRF2 receptors in the control of restraint-evoked cardiovascular responses, both receptors in the BNST are able to modulate arterial pressure, HR, and cutaneous vasoconstriction responses during emotional stress. Furthermore, CRF at the dose of 0.07nmol affected restraint-evoked cardiovascular responses, but microinjection of a higher dose (0.15nmol) did not evoke any change in restraint responses, which indicates an inverted U-shaped dose–response for CRF. As stated above, CRF1 receptor has an excitatory influence in the activity of BNST neurons by enhancing local glutamatergic neurotransmission [42], [43]. However, it has been reported that CRF1 receptor also increases GABAergic neutransmission in the BNST [53], [54]. Nevertheless, electrophysiological studies have demonstrated that increasing doses of CRF evoked greater effects in glutamatergic transmission (maximum increase of 165–200% with 1μM CRF) [42], [43] than in GABAergic neurotransmission (maximum increase of ∼115% with 1μM CRF) [53], indicating that control of GABAergic transmission by CRF1 receptors occurs with reduced potency relative to the modulation of excitatory neurotransmission. Therefore, it is possible that at the higher dose CRF facilitation of GABAergic neurotransmission buffers the increase in local excitatory neurotransmission, thus precluding the emergence of changes in restraint-evoked cardiovascular changes.