Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis regulates the outflow of glucocorticoid hormones under basal conditions and in response to stress. Within the last decade, a large body of evidence has mounted indicating that the endocannabinoid system is involved in the central regulation of the stress response; however, the specific role endocannabinoid signaling plays in phases of HPA axis regulation, and the neural sites of action mediating this regulation, were not mapped out until recently. This review aims to collapse the current state of knowledge regarding the role of the endocannabinoid system in the regulation of the HPA axis to put together a working model of how and where endocannabinoids act within the brain to regulate outflow of the HPA axis. Specifically, we discuss the role of the endocannabinoid system in the regulation of the HPA axis under basal conditions, activation in response to acute stress, and glucocorticoid-mediated negative feedback. Interestingly, there appears to be some anatomical specificity to the role of the endocannabinoid system in each phase of HPA axis regulation, as well as distinct roles of both anandamide and 2-arachidonoylglycerol in these phases. Overall, the current level of information indicates that endocannabinoid signaling acts to suppress HPA axis activity through concerted actions within the prefrontal cortex, amygdala, and hypothalamus.

Figure 1

Under basal conditions (left panel), there is an anandamide (AEA) tone within the basolateral nucleus of the amygdala (BLA) which gates the presynaptic release of glutamate, through activation of CB₁ receptors on glutamatergic terminals, and thus constrains the excitability of projection neurons of the BLA. In response to stress (right panel), hydrolysis of AEA by fatty acid amide hydrolase (FAAH) increases reducing signalling levels of AEA. This loss of AEA signalling at the CB₁ receptor disinhibits glutamatergic inputs to projection neurons of the BLA, resulting in an increase in the firing activity and outflow of BLA projection neurons. Increased activation of the amygdala will contribute to activation of a stress response, which ultimately increases activation of the HPA axis.

Figure 2

(1) Exposure to stress causes activation of CRH neurosecretory cells within the paraventricular nucleus of the hypothalamus (PVN); (2) CRH stimulates the release of ACTH into the general circulation where it acts on the adrenal gland to induce the synthesis and release of glucocorticoid hormones; (3) Glucocorticoid hormones enter the circulation and penetrate the brain where they activate negative feedback pathways; (4) Within the PVN glucocorticoids cause a rapid release of endocannabinoids which suppress excitatory inputs to the CRH cells in the PVN to contribute to fast-feedback inhibition of the HPA axis. Within the prefrontal cortex (PFC), glucocorticoids cause a delayed increase in endocannabioid mobilization, which suppresses local inhibitory circuits and increases the outflow of projection neurons from the PFC. (5) These projection neurons from the PFC activate inhibitory relay neurons to the PVN to turn off neuronal activation of the PVN and contribute to delayed glucocorticoid negative feedback of the HPA axis. Combined, the recruitment of endocannabinoid signalling acts at both short (PVN) and long (PFC) loops of the negative feedback pathway in the brain.

Figure 3

AEA and 2-AG exhibit a ying-yang relationship with HPA axis activity. Under basal conditions, AEA tonically suppresses HPA axis activity. In response to stress, AEA levels rapidly decline within the amygdala, disinhibiting HPA axis activity and resulting in an increase in glucocorticoid hormone secretion. Glucocorticoid hormones act to increase 2-AG production, which then acts to suppress HPA axis activity through actions in both the hypothalamus (rapid) and prefrontal cortex (delayed). In addition, glucocorticoids also act to normalize AEA levels within the amygdala, and thus remove the disinhibition on the HPA axis and help return HPA function to basal levels.