Chronic Stress Induces Anxiety via an Amygdalar Intracellular Cascade that Impairs Endocannabinoid Signaling

Qin, Zhaohong; Zhou, Xun; Pandey, Nihar R.; Vecchiarelli, Haley A.; Stewart, Chloe; Zhang, Xia; Lagace, Diane C.; Brunel, Jean Michel; Béı̈que, Jean-Claude; Stewart, Alexandre F; Hill, Matthew N.; Chen, Hsiao‐Huei

doi:10.1016/j.neuron.2015.02.015

Cited by 85 publications

(83 citation statements)

References 58 publications

(88 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Chronic stress (see the figure, part c ) has recently been shown to cause an impairment of 2-arachidonoyl glycerol (2-AG) synthesis, through collapse of a signalling cascade in glutamatergic neurons in the BLA, a process involving the activation of a metabotropic glucocorticoid receptor (mGR), leading to increased activity of protein tyrosine phosphatase 1B (PTP1B) via decreased palmitoylation and cytoplasmic activity of its inhibitor, LIM domain only 4 (LMO4; translocation out of dendrite). In consequence, PTP1B shows enhanced inhibition of metabotropic glutamate receptor 5 (mGluR5; also known as GRM5) phosphorylation, resulting in decreased diacylglycerol lipase-α (DAGLα) activity and 2-AG production 162 . Pharmacological inhibition of PTP1B rescues the insufficient 2-AG production and the anxiety-like phenotype after chronic stress 162 .…”

Section: Discussionmentioning

confidence: 99%

The endocannabinoid system in guarding against fear, anxiety and stress

et al. 2015

View full text Add to dashboard Cite

The endocannabinoid (eCB) system has emerged as a central integrator linking the perception of external and internal stimuli to distinct neurophysiological and behavioural outcomes (such as fear reaction, anxiety and stress-coping), thus allowing an organism to adapt to its changing environment. eCB signalling seems to determine the value of fear-evoking stimuli and to tune appropriate behavioural responses, which are essential for the organism’s long-term viability, homeostasis and stress resilience; and dysregulation of eCB signalling can lead to psychiatric disorders. An understanding of the underlying neural cell populations and cellular processes enables the development of therapeutic strategies to mitigate behavioural maladaptation.

show abstract

Section: Discussionmentioning

confidence: 99%

The endocannabinoid system in guarding against fear, anxiety and stress

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Similar to this approach, a noncanonical pathway of eCB metabolism has recently been identified to potentially be important for the regulation of eCB signaling under conditions of chronic stress. Here the protein-tyrosine phosphatase 1B (PTP1B) was found to regulate eCB production through an mGluR5-dependent pathway, which was increased following chronic stress, and inhibition of PTP1B was found to partially rescue the stressinduced reductions in amygdalar eCB levels and reverse stress-induced anxiety (Qin et al, 2015). As such, the possibility of therapeutic interventions of the eCB system in the context of stress-related psychiatric conditions opens many doors to novel therapeutics.…”

Section: Hpa Response Terminationmentioning

confidence: 99%

Neurobiological Interactions Between Stress and the Endocannabinoid System

Morena

Patel

Bains

et al. 2015

Neuropsychopharmacol

510

496

View full text Add to dashboard Cite

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.

show abstract

“…Chronically stressed mice show decreased 2-AG production in glutamatergic neurons of the basolateral amygdala and subsequent anxiety. This is due to an increased activity of protein tyrosine phosphatase 1B (PTP1B) and enhanced inhibition of mGluR5 phosphorylation, resulting in decreased DAGL␣ activity (703).…”

Section: Mood and Emotionsmentioning

confidence: 99%

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

377

337

View full text Add to dashboard Cite

Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one ⌬ 9 -tetrahydrocannabinol, and 2) the adaptive prohomeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.

show abstract

Chronic Stress Induces Anxiety via an Amygdalar Intracellular Cascade that Impairs Endocannabinoid Signaling

Cited by 85 publications

References 58 publications

The endocannabinoid system in guarding against fear, anxiety and stress

The endocannabinoid system in guarding against fear, anxiety and stress

Neurobiological Interactions Between Stress and the Endocannabinoid System

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

Contact Info

Product

Resources

About