Meet Your Stress Management Professionals: The Endocannabinoids

Abstract

The endocannabinoid signaling system (ECSS) is altered by exposure to stress and mediates and modulates the effects of stress on the brain. Considerable preclinical data support critical roles for the endocannabinoids and their target, the CB1 cannabinoid receptor, in the adaptation of the brain to repeated stress exposure. Chronic stress exposure increases vulnerability to mental illness, so the ECSS has attracted attention as a potential therapeutic target for the prevention and treatment of stress-related psychopathology. We discuss human genetic studies indicating that the ECSS contributes to risk for mental illness in those exposed to severe stress and trauma early in life, and we explore the potential difficulties in pharmacological manipulation of the ECSS.

Keywords: 2-arachidonoylglycerol; N-arachidonoylethanolamine; cannabinoid receptor; fatty acid amide hydrolase; monoacylglycerol lipase.

Conflict of interest statement

Conflict of Interest:

Cecilia Hillard is a member of the board of scientific directors for Phytecs, Inc and Beryl Therapeutics.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Mechanisms of regulation of the endocannabinoid signaling system.

A: The endocannabinoid signaling system (ECSS) is regulated by endocannabinoid and receptor availability. The CB1 subtype of cannabinoid receptor (CB1R) can be in high and low signaling conformations. The primary mechanism regulating the ratio of receptor conformations is endocannabinoid binding to the receptor. Endocannabinoid concentrations are regulated by the relative rates of their synthesis and degradation. Thus, processes that alter the kinetics and expression of these enzymes are also regulators of CB1R activity. In addition, antagonists block the effects of endocannabinoids through occupation of the binding site, while inverse agonists block endocannabinoid binding and promote the low signaling conformation. Persistent CB1R activation, particularly by full agonists, can cause CB1R desensitization temporarily by receptor internalization or post-translational modification or more long-term via receptor down-regulation. B: Structures and primary pathways for the synthesis and degradation of the endocannabinoids. N-Arachidonoylethanolamine (AEA) is synthesized from a low abundance lipid (N-arachidonoyl-phosphatidylethanolamine; NAPE) through the actions of a NAPE-specific phospholipase D (PLD), with the liberation of phosphatidic acid (PA). AEA is hydrolyzed to free arachidonic acid (AA) and ethanolamine (EA) by the serine hydrolase, fatty acid amide hydrolase (FAAH). 2-Arachidonoylglycerol (2-AG) is synthesized from diacylglycerol (with AA in the sn-2 position) through the actions of diacylglycerol lipase (DAG-Lipase) which results in the release of the fatty acid at the sn-1 position and 2-AG as the products. 2-AG is catabolized by hydrolysis of the ester bond by monoacylglycerol lipase (MGL) with the release of free AA and glycerol.

Figure 2:. Mechanisms linking stress exposure to changes in CB1R-regulation of synaptic signaling.

On the left hand side, stress exposure results in increased CNS glucocorticoid (GC) concentrations, which activate glucocorticoid receptors (GR) located on the plasma membrane. GR signaling triggers the synthesis of 2-arachidonoylglycerol (2-AG) which diffuses from the postsynaptic dendrite of the synthetic neuron to activate CB1 cannabinoid receptors (CB1R) on axon terminals in the immediate vicinity. The result of CB1R binding by 2-AG is reduced neurotransmitter (NT) release. On the right side, stress exposure induces release of corticotropin-releasing hormone (CRH), which binds to the G protein-coupled receptor CRHR1. CRHR1 activation results in a rapid enhancement in the activity of fatty acid amide hydrolase (FAAH), resulting in increased catabolism of N-arachidonoylethanolamine (AEA). AEA synthesis is constitutive and likely exerts tonic activation of CB1R, holding NT release low at synapses regulated by this mechanism. Activation of FAAH results in reduced AEA concentrations, leading to reduced CB1R signaling and increased NT release.

Figure 3.. Selected mechanisms by which the endocannabinoid signaling system (ECSS) affects responses to stress exposure.

The green arrows indicate acute responses to stress exposure, which include activation of the hypothalamic-pituitary-adrenal axis (HPA axis); activation of the sympathetic nervous system (SNS), which results in the release of norepinephrine (NE) from sympathetic terminals and epinephrine (Epi) from the adrenal medulla; and enhanced memory of the traumatic event. The gray arrows indicate some of the consequences of chronic stress exposure, including depressed mood, increased anxiety and persistent fear memories. Our current understanding of the effects of an active and engaged ECSS are indicated over the arrows.