Neurobiological Interactions Between Stress and the Endocannabinoid System

Abstract

Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic-pituitary-adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.

Figures

Figure 1

General model illustrating the retrograde endocannabinoid signaling. Upon release of neurotransmitter (eg, glutamate), postsynaptic depolarization causes increased intracellular Ca2+ levels through activation of AMPA, NMDA receptors and/or Gq-coupled receptors (eg, mGluR1/5) and voltage-gated Ca2+ channels. Intracellular Ca2+ elevation increases endocannabinoid biosynthesis, although there is evidence for Ca2+-independent forms of endocannabinoid synthesis as well. This model illustrates the two primary biosynthetic pathways for anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), respectively. AEA is synthesized from phospholipid precursors (eg phosphatidylethanolamine, PE) by a Ca2+-dependent transacylase, N-acyltransferase (NAT), yielding N-arachidonoyl PE (NAPE). NAPE is then hydrolyzed by a phospholipase D (NAPE-PLD) to yield AEA. Ca2+ influx and/or the activation of Gq-coupled receptors stimulate phospholipase C (PLC), which hydrolyses phosphatidylinositol (PI) into diacylglycerol (DAG). DAG is converted to 2-AG by diacylglycerol lipase (DGL). AEA and 2-AG then migrate from postsynaptic neurons to bind presynaptic-located cannabinoid type 1 (CB1) receptors. Once activated, CB1 receptors couple through Gi/o proteins to inhibit adenylyl cyclase and regulate ion channels and ultimately suppress neurotransmitter release. Endocannabinoid signaling is then terminated by degrading enzymes. AEA is mainly hydrolyzed to arachidonic acid (AA) and ethanolamine (EA) by fatty acid amide hydrolase (FAAH), located postsynaptically. 2-AG is hydrolyzed presynaptically to AA and glycerol (Glyc) by monoacylglycerol lipase (MAGL), which accounts for ~85% of 2-AG hydrolysis, and postsynaptically by alpha-beta-hydrolase 6/12 (ABHD6/12), which accounts for the remainder of 2-AG hydrolysis. AEA and 2-AG are also oxygenated by cyclo-oxygenase 2 (COX-2) to form prostaglandin-ethanolamides (PG-EAs) and prostaglandin-glycerols (PG-Gs).

Figure 2

Temporal dynamics of anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) changes following stress exposure. Acute exposure to stress rapidly increases corticotropin-releasing hormone (CRH) signaling in the basolateral amygdala (BLA). The subsequent activation of CRHR1 receptors rapidly increases the enzymatic activity of fatty acid amide hydrolase (FAAH), resulting in a decrease of the inhibitory tone of AEA, which in turn contributes to the activation of hypothalamic–pituitary–adrenal (HPA) axis and stress-related behavioral responses. The delayed increase of brain corticosterone levels stimulates the release of 2-AG in the medial prefrontal cortex (mPFC) and paraventricular nucleus of hypothalamus (PVN). This increased 2-AG signaling at CB1 receptors contributes to negative-feedback inhibition of the HPA axis and termination of stress response.

Figure 3

Schematic illustration of behavioral outputs regulated by the interaction between stress and endocannabinoids. Exposure to stress, both acute and chronic, generally results in a bidirectional regulation of anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with AEA being reduced and 2-AG being increased from stress. Although the behavioral outputs regulated by AEA and 2-AG in some cases likely overlap, the decline in AEA signaling seems to mainly contribute not only to the manifestation of an anxiety state, the activation of the HPA axis, the suppression of neurogenesis in the hippocampus, and an impairment in fear extinction but also may have a role in the development of anhedonia and hyperalgesia. Unlike AEA, the behavioral influences of 2-AG are less characterized as selective tools for manipulating 2-AG signaling have only been recently developed. The stress-induced increase in 2-AG is believed to buffer and constrain the effects of stress on the brain, particularly by contributing to termination of stress-induced HPA axis activation and promoting habituation to stress, to possibly contribute to the ability of acute stress to shift synaptic plasticity, to mediate stress impairing effects on memory retrieval, and contribute to stress-induced analgesia. *Interestingly, with respect to memory consolidation, it appears that the stress/pain associated with the training procedure (ie, footshock exposure) leads to an increase in limbic AEA levels that, in turn, contributes to enhance aversive memory consolidation, distinguishing this effect from the other noted effects that are related to the decline in AEA signaling typically seen following stress.