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

Lucas Gomes-De-Souza,Michelle M Mendonça,Carlos C Crestani,Willian Costa-Ferreira,Carlos H Xavier

doi:10.1038/s41598-021-95401-z

Abstract

The endocannabinoid neurotransmission acting via local CB1 receptor in the bed nucleus of the stria terminalis (BNST) has been implicated in behavioral and physiological responses to emotional stress. However, the neural network related to this control is poorly understood. In this sense, the lateral hypothalamus (LH) is involved in stress responses, and BNST GABAergic neurons densely innervate this hypothalamic nucleus. However, a role of BNST projections to the LH in physiological responses to stress is unknown. Therefore, using male rats, we investigated the role of LH GABAergic neurotransmission in the regulation of cardiovascular responses to stress by CB1 receptors within the BNST. We observed that microinjection of the selective CB1 receptor antagonist AM251 into the BNST decreased the number of Fos-immunoreactive cells within the LH of rats submitted to acute restraint stress. Treatment of the BNST with AM251 also enhanced restraint-evoked tachycardia. Nevertheless, arterial pressure increase and sympathetically-mediated cutaneous vasoconstriction to restraint was not affected by CB1 receptor antagonism within the BNST. The effect of AM251 in the BNST on restraint-evoked tachycardia was abolished in animals pretreated with the selective GABAA receptor antagonist SR95531 in the LH. These results indicate that regulation of cardiovascular responses to stress by CB1 receptors in the BNST is mediated by GABAergic neurotransmission in the LH. Present data also provide evidence of the BNST endocannabinoid neurotransmission as a mechanism involved in LH neuronal activation during stressful events.

Highlights

The endocannabinoid neurotransmission acting via local CB1 receptor in the bed nucleus of the stria terminalis (BNST) has been implicated in behavioral and physiological responses to emotional stress
In this sense, considering recent evidence that regulation of restraint-evoked tachycardia by BNST CB1 receptor is mediated by inhibition of local glutamatergic neurotransmission[35], we investigated the hypothesis that the antagonism of C B1 receptor within the BNST decreases local neuronal activation within the lateral hypothalamus (LH) as resulted of increased activation of BNST GABAergic neurons projecting to the HL, which in turn increases heart rate (HR) response to stress
Effect of GABAA receptor antagonism in the LH in changes on arterial pressure and HR reactivity to acute restraint stress evoked by CB1 receptor blockade in the BNST

Summary

Introduction

The endocannabinoid neurotransmission acting via local CB1 receptor in the bed nucleus of the stria terminalis (BNST) has been implicated in behavioral and physiological responses to emotional stress. These morphofunctional evidence, taken together with evidence stated above of an inhibitory role of LH in tachycardia to r estraint[27], supported the idea that the LH might be part of the neural pathway related to the inhibitory control of restraintevoked tachycardia by BNST endocannabinoid neurotransmission In this sense, considering recent evidence that regulation of restraint-evoked tachycardia by BNST CB1 receptor is mediated by inhibition of local glutamatergic neurotransmission[35], we investigated the hypothesis that the antagonism of C B1 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

Methods

Results

Conclusion