Cannabinoid and GABA modulation of sympathetic nerve activity and blood pressure in the dorsal periaqueductal gray of the rat

Abstract

Sympathoexcitation and increased blood pressure evoked by central networks integrating defensive behavior are fundamental to the acute stress response. A balance between excitatory glutamatergic and inhibitory GABAergic neurotransmission in the dorsal periaqueductal gray (dPAG) results in a tonic level of activity in the alerting system. Neuromodulators such as endocannabinoids have been shown to influence the sympathoexcitatory and pressor components of acute stress in the dPAG, exemplified by the defense response as a model, but the mechanism of integration remains unknown. The present study examines the role of GABA and its interaction with endocannabinoids in modulating sympathetic nerve activity and blood pressure related to the defense response. Microinjection of the broad-spectrum excitatory amino acid dl-homocysteic acid (DLH) identified sites of the defense pathway in the dPAG from which an increase in renal sympathetic nerve activity and blood pressure could be evoked, and subsequent microinjections were made at the same site through a multibarrelled micropipette. Blockade of GABAA receptors or microinjection of the cannabinoid 1 receptor agonist anandamide elicited a renal sympathoexcitation and pressor response. Prior microinjection of the GABAA receptor antagonist gabazine attenuated the sympathoexcitation and pressor response associated with anandamide microinjection. In contrast, the sympathetic response to DLH was enhanced by GABAA receptor blockade. These data demonstrate that sympathoexcitatory neurons in the dPAG are under tonic inhibition by GABA and that endocannabinoids modulate this GABAergic neurotransmission to help regulate components of the defense response.

Stress regulates endocannabinoid-CB1 receptor signaling

“…Mobilization of ECS in the rat dorsal periaqueductal gray (PAG) enhances SNS activation [113, 114]. CB1R are found in the PAG [115] and microinjection of AEA into the dorsal PAG increases renal sympathetic nerve activity within 30 sec of injection [113].…”

“…CB1R are found in the PAG [115] and microinjection of AEA into the dorsal PAG increases renal sympathetic nerve activity within 30 sec of injection [113]. These effects are inhibited by CB1R antagonist pretreatment and are consistent with CB1R-mediated inhibition of GABA release [114]. Microinjection of CB1R antagonist into the dorsal PAG also inhibits SNS responses evoked by hypothalamic stimulation [113].…”

Components of the cannabinoid system in the dorsal periaqueductal gray are related to resting heart rate

“…While endocannabinoid modulation of sympathetic outflow is associated with stress responses in the dPAG, (12, 13), it is not known whether endocannabinoids in this midbrain region contribute to ongoing sympathetic tone through this circuitry, Therefore, the present study was undertaken to determine whether endocannabinoid signaling in the dPAG contributes to autonomic and cardiovascular regulation under resting conditions.…”

“…Cannabinoids can enhance autonomic activity and cardiovascular parameters through endocannabinoid signaling in the dorsal periaqueductal gray (dPAG), a highly integrative region, the activation of which is associated with enhanced sympathetic and cardiovascular regulation in emotional behaviors (28). Endocannabinoids function in the dPAG by inhibiting tonically active GABAergic neurons to exert a profound activation of output neurons, leading to an increase in sympathetic nerve activity and blood pressure (12, 13). …”

Involvement of non-NMDA glutamate receptors of the hypothalamic paraventricular nucleus in the cardiovascular response to the microinjection of noradrenaline into the dorsal periaqueductal gray area of rats

“…There are previous studies showing that either electrical or chemical stimulation with the broad-spectrum excitatory amino acid dl-homocysteic acid (DLH) or glutamate (200 nL) or NMDA (200 nL) in the dPAG induce a panic-related defensive response and/or anxiety-like behavior in animals (Ballesteros et al, 2014;Camplesi et al, 2012;de Almeida et al, 2006;Dean, 2011;Krieger and Graeff, 1985;Reimer et al, 2012). However, another set of studies have demonstrated that there is a behavior-related distinction between columns of the PAG, suggesting that the lateral and dorsolateral (dlPAG) regions (Bandler and Shipley, 1994;Bandler et al, 2000;Carrive, 1993;da Silva et al, 2006) are associated with behavioral reactions, while the dorsomedial region (dmPAG) is not (Pelosi et al, 2012).…”