A previous study conducted by our

A previous study conducted by our group demonstrated that bilateral BNST neurotransmission inhibition evoked by local treatment with CoCl2 enhanced the HR increase evoked by restraint stress without affecting the arterial pressure response [14]. Similar effect was observed after BNST treatment with a selective α1-adrenoceptor antagonist (i.e., facilitation of restraint-evoked tachycardiac response without affecting pressor effect) [14], suggesting that the inhibitory role of the BNST in HR response to restraint stress is mediated, at least in part, by the local action of noradrenergic mechanisms. In contrast, present study indicates that activation of CRF1 receptor in the BNST during restraint stress play a facilitatory role in tachycardiac response. Noradrenaline has predominantly an inhibitory influence in the activity of BNST Anhydrotetracycline hydrochloride receptor [36], which is mediated by a facilitation of local GABAergic neurotransmission and inhibition of glutamatergic inputs [37], [38], [39], [40], [41]. In contrast, CRF1 receptor activation enhances excitatory neurotransmission in the BNST [42], [43]. These pieces of evidence support the findings of an opposite influence of BNST CRF1 receptor and α1-adrenoceptors in the restraint-evoked tachycardic response. Present findings bring the first evidence of an influence of the BNST in the arterial pressure and skin temperature responses induced by an unconditioned aversive stimulus. 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 receptor 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.