Cannabinoid receptor type 1 in the bed nucleus of the stria terminalis modulates cardiovascular responses to stress via local N-methyl-D-aspartate receptor/neuronal nitric oxide synthase/soluble guanylate cyclase/protein kinase G signaling

Abstract

Background: Endocannabinoid neurotransmission in the bed nucleus of the stria terminalis is involved in the control of cardiovascular responses to stress. However, the local mechanisms involved is this regulation are not known. Aims: The purpose of this study was to assess an interaction of bed nucleus of the stria terminalis endocannabinoid neurotransmission with local nitrergic signaling, as well as to investigate the involvement of local N-methyl-D-aspartate glutamate receptor and nitric oxide signaling in the control of cardiovascular responses to acute restraint stress by bed nucleus of the stria terminalis endocannabinoid neurotransmission in rats. Methods: The first protocol evaluated the effect of intra-bed nucleus of the stria terminalis microinjection of the selective cannabinoid receptor type 1 receptor antagonist AM251 in nitrite/nitrate content in the bed nucleus of the stria terminalis following restraint stress. The other protocols evaluated the impact of local pretreatment with the selective N-methyl-D-aspartate glutamate receptor antagonist LY235959, the selective neuronal nitric oxide synthase inhibitor Nω-propyl-L-arginine, the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, or the protein kinase G inhibitor KT5823 in restraint-evoked cardiovascular changes following bed nucleus of the stria terminalis treatment with AM251. Results: Bilateral microinjection of AM251 into the bed nucleus of the stria terminalis increased local nitric oxide release during restraint stress. Bed nucleus of the stria terminalis treatment with the cannabinoid receptor type 1 receptor antagonist also enhanced the tachycardia caused by restraint stress, but without affecting arterial pressure increase and sympathetic-mediated cutaneous vasoconstriction. The facilitation of restraint-evoked tachycardia following bed nucleus of the stria terminalis treatment with the cannabinoid receptor type 1 receptor antagonist was completely inhibited by local pretreatment with LY235959, Nω-propyl-L-arginine, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, or KT5823. Conclusions: Our results provide evidence that bed nucleus of the stria terminalis endocannabinoid neurotransmission inhibits local N-methyl-D-aspartate/neuronal nitric oxide synthase/soluble guanylate cyclase/protein kinase G signaling, and this mechanism is involved in the control of the cardiovascular responses to stress.

Lateral hypothalamus involvement in control of stress response by bed nucleus of the stria terminalis endocannabinoid neurotransmission in male rats

“…As stated in the Introduction, previous studies provided evidence of GABAergic inputs within the LH arising from the BNST 33 , 34 . These neuroanatomical evidence, taken together with results mentioned above that CB 1 receptor activation during aversive threats acts mainly inhibiting glutamatergic terminals during aversive threats 16 , 17 , 35 indicate that the decrease in number of Fos-immunoreactive cells in the LH observed in the present study in animals treated with the CB 1 receptor antagonist in the BNST might be the resulted of an increased local glutamatergic neurotransmission, which in turn increase activation of BNST GABAergic neurons projecting to the LH. The hypothesis that GABAergic connection with the LH mediates the inhibitory control of BNST CB 1 receptor was further supported by demonstration that LH pretreatment with the GABA A receptor antagonist SR95531 completely inhibited the facilitation of HR increase to restraint stress caused by BNST treatment with the CB 1 receptor antagonist AM251.…”

“…For instance, previous findings identified that CB 1 receptor blockade enhanced stress-evoked c-fos mRNA in the BNST 16 , 17 . Besides, we reported recently that the facilitated tachycardia to restraint stress following BNST treatment with AM251 was inhibited by local NMDA glutamate receptor antagonism within the BNST 35 . The idea that control of cardiovascular responses to restraint by BNST CB 1 receptor is mediated by interaction with local glutamatergic neurotransmission is further supported by evidence that BNST NMDA glutamate receptor plays a facilitatory influence in restraint-evoked HR response without affecting pressor and tail skin temperature changes 39 , 40 .…”

“…Vasomotor sympathetic activity activation during aversive threats decreases cutaneous blood flow 66 that in turn reduces cutaneous temperature 67 . Therefore, the drop in tail cutaneous temperature was evaluated as an indirect measurement of vasomotor sympathetic response in cutaneous beds during restraint stress 13 , 35 , 67 .…”

“…These morphofunctional evidence, taken together with evidence stated above of an inhibitory role of LH in tachycardia to restraint 27 , supported the idea that the LH might be part of the neural pathway related to the inhibitory control of restraint-evoked tachycardia by BNST endocannabinoid neurotransmission. In this sense, considering recent evidence that regulation of restraint-evoked tachycardia by BNST CB 1 receptor is mediated by inhibition of local glutamatergic neurotransmission 35 , we investigated the hypothesis that the antagonism of CB 1 receptor within the BNST decreases local neuronal activation within the LH as resulted of increased activation of BNST GABAergic neurons projecting to the HL, which in turn increases HR response to stress.…”

NMDA receptors in the insular cortex modulate cardiovascular and autonomic but not neuroendocrine responses to restraint stress in rats

“…The animals were kept under a 12-h/12-h light/dark cycle (lights on between 7:00 AM and 7:00 PM) and had free access to water and standard rat food. We chose all group size of all experiments shown in the present study based on previously reported data which are comparable with our experiments (Barretto-de-Souza, Benini, Reis-Silva, & Crestani, 2021;Gomes-de-Souza, Costa-Ferreira, Oliveira, Benini, & Crestani, 2020).…”