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Endocannabinoid Signaling and the Hypothalamic‐Pituitary‐Adrenal Axis

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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. © 2017 American Physiological Society. Compr Physiol 7:1‐15, 2017.

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Figure 1. Figure 1. Two eCBs act at CB1 and CB2 receptors with differing affinities and efficacies. AEA, N‐arachidonylethanolamine; CB1R, subtype 1 of the cannabinoid receptor; CB2R, subtype 2 of the cannabinoid receptor; 2‐AG, 2‐arachidonoylglycerol. Affinity refers to the ability of the eCB and receptor to form a bound complex and efficacy refers to the ability of the eCB to induce signaling via the receptor.
Figure 2. Figure 2. (A) Biosynthetic and catabolic pathways for AEA. (B) Biosynthetic and catabolic pathways for 2‐AG. AA, arachidonic acid; Abhd, alpha‐beta‐hydrolase domain protein; DAG, diacylglycerol; DAGL, diacylglycerol lipase; EA, ethanolamine; FAAH, fatty acid amide hydrolase; GDE1, glycerophosphodiesterase 1; GP‐AEA, glycerophospho‐AEA; NAAA, N‐acylethanolamine‐hydrolyzing acid amidase; NAPE‐PLD, N‐acyl phosphatidylethanolamine‐specific phospholipase D; NAT, N‐acyltransferase; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PIP2, phosphatidylinositol bis phosphate; PI‐PLC, phosphatidylinositol‐specific phospholipase C; PLA/AT, phospholipase A/acyltransferase; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PTPN22, protein tyrosine phosphatase, nonreceptor type 22; SHIP1, Src homology 2‐containing inositol phosphatase‐1.
Figure 3. Figure 3. (A) Components of eCB signaling are expressed at the synapse. Shown is the common pattern of distribution of the CB1R and the proteins involved in the synthesis and degradation of the eCBs AEA and 2‐AG. See the legend to Figure 2 for abbreviations. (B) CB1R, via Gαi/0, inhibit neurotransmitter release via multiple mechanisms. Inhibition of the opening of voltage‐gated calcium channels results in the short‐term changes in synaptic plasticity of depolarization‐induced suppression of inhibition (DSI) or excitation (DSE). Inhibition of cAMP generation and the subsequent reduction in activation of protein kinase A results in long term depression of inhibition (iLTD) and long term depression of excitation (LTD).
Figure 4. Figure 4. mGluR and 2‐AG regulation of synaptic activity. (A) In this scenario, the CB1R are present on glutamatergic terminals so increased 2‐AG synthesis in response to mGluR receptor activation results in inhibition of glutamate release. As a result, the synaptic balance is shifted to reduced excitation and increased inhibition (A1). (B) In this scenario, the CB1R are present on GABA terminals and increased 2‐AG synthesis results in inhibition of GABA release. As a result, the synaptic balance is shifted to greater excitation and reduced inhibition. 2‐AG, 2‐arachidonoylglycerol; CB1R, subtype 1 of the cannabinoid receptor; Glu, glutamate; mGluR, metabotropic glutamate receptor. Other abbreviations are in the legend to Figure 2.
Figure 5. Figure 5. Hypothesized expression and function of CB1R along the HPA axis. Data described in the text support the expression and hypothesized inhibitory roles of the CB1R at all three levels of the HPA axis. In the paraventricular nucleus, CB1R have been identified on both glutamatergic and GABAergic terminals. Corticotropes of the anterior pituitary express CB1R, which we hypothesize, could inhibit CRH‐induced activation of adenylyl cyclase (AC), thereby reducing cAMP concentrations. In the adrenal gland, CB1R have been identified on cortical cells, where we hypothesize they could oppose the elevation of cAMP induced by ACTH acting through melanocortin 2 receptors (MC2R). CB1R have also been proposed to be present on medullary cells of the adrenal gland and to inhibit the release of epinephrine (EPI) from these cells. This would result in reduced activation of ß‐adrenergic receptors (ßAR) on the cortical cells.
Figure 6. Figure 6. High‐efficacy cannabinoid agonists have biphasic effects on HPA axis activation by stress, while the partial agonist, THC, and antagonists increase HPA axis activation. Our hypothesis for these findings is displayed in this figure. The CB1R‐mediated inhibition of HPA axis activation by stress has high eCB tone (as is shown in Fig. 7). As a result, only high efficacy agonists can increase this tone further. Low‐efficacy agonists and antagonists will inhibit this tone and “uncover” the HPA axis potentiating CB1R function. We hypothesize based on the data available that the HPA axis potentiating CB1R has low eCB tone.
Figure 7. Figure 7. Depiction of the amygdalar AEA gate hypothesis. According to this hypothesis, AEA concentrations are high at rest, resulting in tonic activation of CB1R on glutamatergic terminals in the basolateral amygdala. This prevents glutamate release. Increased CRH as occurs during stress results in activation of FAAH by an as‐yet unidentified mechanism, resulting in reduced AEA and relief of AEA/CB1R‐mediated inhibition of glutamate release.
Figure 8. Figure 8. In both the prefrontal cortex and hippocampus, studies demonstrate that 2‐AG synthesis is enhanced by glucocorticoid (CORT) through activation of GRs. CB1R on GABAergic terminals are subsequently activated, resulted in reduced GABA release and disinhibition of glutamatergic projection neurons. These neurons project onto GABAergic neurons in other areas of the brain which ultimately inhibit CRH release.


Figure 1. Two eCBs act at CB1 and CB2 receptors with differing affinities and efficacies. AEA, N‐arachidonylethanolamine; CB1R, subtype 1 of the cannabinoid receptor; CB2R, subtype 2 of the cannabinoid receptor; 2‐AG, 2‐arachidonoylglycerol. Affinity refers to the ability of the eCB and receptor to form a bound complex and efficacy refers to the ability of the eCB to induce signaling via the receptor.


Figure 2. (A) Biosynthetic and catabolic pathways for AEA. (B) Biosynthetic and catabolic pathways for 2‐AG. AA, arachidonic acid; Abhd, alpha‐beta‐hydrolase domain protein; DAG, diacylglycerol; DAGL, diacylglycerol lipase; EA, ethanolamine; FAAH, fatty acid amide hydrolase; GDE1, glycerophosphodiesterase 1; GP‐AEA, glycerophospho‐AEA; NAAA, N‐acylethanolamine‐hydrolyzing acid amidase; NAPE‐PLD, N‐acyl phosphatidylethanolamine‐specific phospholipase D; NAT, N‐acyltransferase; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PIP2, phosphatidylinositol bis phosphate; PI‐PLC, phosphatidylinositol‐specific phospholipase C; PLA/AT, phospholipase A/acyltransferase; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PTPN22, protein tyrosine phosphatase, nonreceptor type 22; SHIP1, Src homology 2‐containing inositol phosphatase‐1.


Figure 3. (A) Components of eCB signaling are expressed at the synapse. Shown is the common pattern of distribution of the CB1R and the proteins involved in the synthesis and degradation of the eCBs AEA and 2‐AG. See the legend to Figure 2 for abbreviations. (B) CB1R, via Gαi/0, inhibit neurotransmitter release via multiple mechanisms. Inhibition of the opening of voltage‐gated calcium channels results in the short‐term changes in synaptic plasticity of depolarization‐induced suppression of inhibition (DSI) or excitation (DSE). Inhibition of cAMP generation and the subsequent reduction in activation of protein kinase A results in long term depression of inhibition (iLTD) and long term depression of excitation (LTD).


Figure 4. mGluR and 2‐AG regulation of synaptic activity. (A) In this scenario, the CB1R are present on glutamatergic terminals so increased 2‐AG synthesis in response to mGluR receptor activation results in inhibition of glutamate release. As a result, the synaptic balance is shifted to reduced excitation and increased inhibition (A1). (B) In this scenario, the CB1R are present on GABA terminals and increased 2‐AG synthesis results in inhibition of GABA release. As a result, the synaptic balance is shifted to greater excitation and reduced inhibition. 2‐AG, 2‐arachidonoylglycerol; CB1R, subtype 1 of the cannabinoid receptor; Glu, glutamate; mGluR, metabotropic glutamate receptor. Other abbreviations are in the legend to Figure 2.


Figure 5. Hypothesized expression and function of CB1R along the HPA axis. Data described in the text support the expression and hypothesized inhibitory roles of the CB1R at all three levels of the HPA axis. In the paraventricular nucleus, CB1R have been identified on both glutamatergic and GABAergic terminals. Corticotropes of the anterior pituitary express CB1R, which we hypothesize, could inhibit CRH‐induced activation of adenylyl cyclase (AC), thereby reducing cAMP concentrations. In the adrenal gland, CB1R have been identified on cortical cells, where we hypothesize they could oppose the elevation of cAMP induced by ACTH acting through melanocortin 2 receptors (MC2R). CB1R have also been proposed to be present on medullary cells of the adrenal gland and to inhibit the release of epinephrine (EPI) from these cells. This would result in reduced activation of ß‐adrenergic receptors (ßAR) on the cortical cells.


Figure 6. High‐efficacy cannabinoid agonists have biphasic effects on HPA axis activation by stress, while the partial agonist, THC, and antagonists increase HPA axis activation. Our hypothesis for these findings is displayed in this figure. The CB1R‐mediated inhibition of HPA axis activation by stress has high eCB tone (as is shown in Fig. 7). As a result, only high efficacy agonists can increase this tone further. Low‐efficacy agonists and antagonists will inhibit this tone and “uncover” the HPA axis potentiating CB1R function. We hypothesize based on the data available that the HPA axis potentiating CB1R has low eCB tone.


Figure 7. Depiction of the amygdalar AEA gate hypothesis. According to this hypothesis, AEA concentrations are high at rest, resulting in tonic activation of CB1R on glutamatergic terminals in the basolateral amygdala. This prevents glutamate release. Increased CRH as occurs during stress results in activation of FAAH by an as‐yet unidentified mechanism, resulting in reduced AEA and relief of AEA/CB1R‐mediated inhibition of glutamate release.


Figure 8. In both the prefrontal cortex and hippocampus, studies demonstrate that 2‐AG synthesis is enhanced by glucocorticoid (CORT) through activation of GRs. CB1R on GABAergic terminals are subsequently activated, resulted in reduced GABA release and disinhibition of glutamatergic projection neurons. These neurons project onto GABAergic neurons in other areas of the brain which ultimately inhibit CRH release.
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Cecilia J. Hillard, Margaret Beatka, Jenna Sarvaideo. Endocannabinoid Signaling and the Hypothalamic‐Pituitary‐Adrenal Axis. Compr Physiol 2016, 7: 1-15. doi: 10.1002/cphy.c160005