Endocannabinoid Signaling and the Hypothalamic‐Pituitary‐Adrenal Axis

Abstract

The elucidation of Δ9-tetrahydrocannabinol as the active principal of Cannabis sativa in 1963 initiated a fruitful half-century of scientific discovery, culminating in the identification of the endocannabinoid signaling system, a previously unknown neuromodulatory system. A primary function of the endocannabinoid signaling system is to maintain or recover homeostasis following psychological and physiological threats. We provide a brief introduction to the endocannabinoid signaling system and its role in synaptic plasticity. The majority of the article is devoted to a summary of current knowledge regarding the role of endocannabinoid signaling as both a regulator of endocrine responses to stress and as an effector of glucocorticoid and corticotrophin-releasing hormone signaling in the brain. We summarize data demonstrating that cannabinoid receptor 1 (CB1R) signaling can both inhibit and potentiate the activation of the hypothalamic-pituitary-adrenal axis by stress. We present a hypothesis that the inhibitory arm has high endocannabinoid tone and also serves to enhance recovery to baseline following stress, while the potentiating arm is not tonically active but can be activated by exogenous agonists. We discuss recent findings that corticotropin-releasing hormone in the amygdala enables hypothalamic-pituitary-adrenal axis activation via an increase in the catabolism of the endocannabinoid N-arachidonylethanolamine. We review data supporting the hypotheses that CB1R activation is required for many glucocorticoid effects, particularly feedback inhibition of hypothalamic-pituitary-adrenal axis activation, and that glucocorticoids mobilize the endocannabinoid 2-arachidonoylglycerol. These features of endocannabinoid signaling make it a tantalizing therapeutic target for treatment of stress-related disorders but to date, this promise is largely unrealized.

Circulating Endocannabinoids: From Whence Do They Come and Where are They Going?

“…These very interesting findings suggest that 2-AG is brain-derived and driven by excitatory signaling, which is consistent with considerable data that glutamate increases 2-AG synthesis (Hillard, 2015). These findings are also consistent with the role of 2-AG to reduce HPA axis activation (Hillard et al, 2016). It is interesting that circulating 2-AG concentrations and measures of positive emotion were not associated in this study, given the evidence below that 2-AG has been found in other studies to be negatively associated with symptoms of depression.…”

Cannabinoid Modulation of the Stressed Hippocampus

“…Moreover, besides the hippocampus, other brain regions such as the prefrontal cortex, amygdala (Hill et al, 2010 ), nucleus accumbens (Bosch-Bouju et al, 2016 ), the paraventricular nucleus of the hypothalamus (Wamsteeker et al, 2010 ), lateral habenula (Park et al, 2017 ) and the periaqueductal gray matter (Moreira et al, 2009 ), are involved in stress-induced behavioral and neuroplastic consequences. These regions are modulated by eCBs and, therefore, are also potential therapeutic targets for cannabinoid drugs (For additional information about this topic, please read the excellent reviews by Gorzalka and Hill ( 2009 ), Riebe and Wotjak ( 2011 ), Hillard et al ( 2016 ), Lutz et al ( 2016 ) and Balsevich et al ( 2017 ).…”

“…Considering that stress-induced HPA axis activation and consequent corticosterone release modulate the production of eCB and CB 1 function (Hillard et al, 2016 ), it is possible that cannabinoids and glucocorticoids interact to control stress responses. Glucocorticoid hormones and their receptors (mineralocorticoid-MR and glucocorticoid receptors-GR) are abundantly expressed in the hippocampus (Herman et al, 1993 ), where, together with eCBs, they control the negative feedback regulation of the HPA axis (Hillard et al, 2016 ). Several pieces of evidence indicate that glucocorticoids and the eCB system interact to control emotional, physiological, and adaptive responses to stress.…”

Integrating Endocannabinoid Signaling and Cannabinoids into the Biology and Treatment of Posttraumatic Stress Disorder

“…eCBs have been heavily implicated in modulation of the physiological and behavioral sequelae of stress exposure, particularly with respect to neuroendocrine aspects of the stress response (for a more in-depth review on this subject see Hillard et al (2016); Lutz et al (2015); Morena et al (2016b)). With respect to the HPA-axis, eCB signaling appears to be an important modulator of activation and termination of the HPA-axis function.…”