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.

Peripheral and central CB1 cannabinoid receptors control stress-induced impairment of memory consolidation

“…Thus, glucocorticoids enhance the production of endocannabinoids to counteract the activity of the HPA axis in many brain regions, including the hippocampus, the prefrontal cortex, and the hypothalamus (16,24). Overall, endocannabinoid production is induced by acute stress and acts by buffering stress-induced behavioral and endocrine stress effects (16,17,23).In this study we reveal a mechanism mediating stress-induced impairment of object-recognition memory consolidation. Using a combination of acute systemic and local pharmacological approaches and newly generated mouse lines, we found that peripheral and hippocampal CB1 receptors in dopamine β-hydroxylase (DBH)-expressing cells (i.e., adrenergic/noradrenergic cells) are both necessary and sufficient to impair object-recognition memory consolidation produced by acute stress.…”

“…The endocannabinoid system is an endogenous neuromodulatory system playing a relevant role in the regulation of the stress response (13)(14)(15)(16)(17)(18). Endocannabinoids, such as 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide; AEA), act mainly at two types of cannabinoid receptors, cannabinoid type-1 (CB1) and type-2 (CB2) receptors.…”

“…Thus, glucocorticoids enhance the production of endocannabinoids to counteract the activity of the HPA axis in many brain regions, including the hippocampus, the prefrontal cortex, and the hypothalamus (16,24). Overall, endocannabinoid production is induced by acute stress and acts by buffering stress-induced behavioral and endocrine stress effects (16,17,23).…”

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

“…The activation of the CB1 receptors have analgesic effects at the peripheral sensory afferents, in the dorsal horn of the spinal cord, the periaqueductal grey (PAG) and the brainstem (Woodhams et al 2015). In addition, endocannabinoids are indispensable in the development of acute stress induced analgesia (Morena et al 2016), and the downregulation of endocannabinoid signalling is an important mechanism in the development of chronic stress induced hyperalgesia (Jennings et al 2015; Lomazzo et al 2015; Rea et al 2014). However, more and more evidence suggests that endocannabinoids mainly influence the affective component of pain, in which amygdala activity has a pivotal role, compared to the sensory aspects (Lee et al 2013).…”

Impact of Stress on the Brain: Pathology, Treatment and Prevention

“…How fear is modulated by stress is beginning to be understood at a variety of levels, including both neural circuitry and underlying molecular mechanisms. A particularly interesting set of findings over the past few years has revealed how the endogenous cannabinoid system is involved in both extinction of fear and in modulating the stress response, as reviewed in detail at the end of this section (Morena et al, 2016).…”