Blockade of 2‐arachidonoylglycerol hydrolysis produces antidepressant‐like effects and enhances adult hippocampal neurogenesis and synaptic plasticity

Zhang, Zhen; Wang, Wei; Zhong, Peng; Liu, Sarah J.; Long, Jonathan Z.; Zhao, Li; Gao, Haiqing; Cravatt, Benjamin F.; Liu, Qingsong

doi:10.1002/hipo.22344

Cited by 75 publications

(64 citation statements)

References 78 publications

(133 reference statements)

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“…Accordingly, chronic stressinduced collapse of eCB signaling may be involved in the development of allostatic load from chronic stress and contribute to the development of psychiatric conditions, such as depression. This hypothesis is consistent with findings that augmenting eCB signaling in the presence of chronic stress can stabilize and curb stress-induced changes in plasticity and produce potential antidepressant-or anxiolytic-like effects (Bortolato et al, 2007;Hill et al, 2013b;Lomazzo et al, 2015;Sumislawski et al, 2011;Zhang et al, 2015;Zhong et al, 2014).…”

Section: Functional Role Of Ecb Signaling In the Neurobiological Effesupporting

confidence: 91%

“…Consistent with this, central genetic 2-AG deficiency results in increased anxiety that can be reversed by acute normalization of 2-AG levels (Shonesy et al, 2014). There is also evidence that potentiation of 2-AG signaling can dampen anxiety induced by chronic stress (Sumislawski et al, 2011;Zhang et al, 2015; but see Lomazzo et al, 2015 for negative findings). These studies clearly support the notion that 2-AG also has a key role in regulating anxiety and stress responsivity.…”

Section: Functional Role Of Ecb Signaling In the Neurobiological Effementioning

confidence: 87%

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Neurobiological Interactions Between Stress and the Endocannabinoid System

Morena

Patel

Bains

et al. 2015

Neuropsychopharmacol

492

496

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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.

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Section: Functional Role Of Ecb Signaling In the Neurobiological Effesupporting

confidence: 91%

Section: Functional Role Of Ecb Signaling In the Neurobiological Effementioning

confidence: 87%

Neurobiological Interactions Between Stress and the Endocannabinoid System

Morena

Patel

Bains

et al. 2015

Neuropsychopharmacol

492

496

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“…Pharmacological blockade of its hydrolyzing enzyme MAGL produces anxiolytic-like effects (479,782,941). Genetic modification by adeno-associated virus-mediated overexpression of MAGL in hippocampal glutamatergic neurons of the mouse resulted in a 50% decrease in 2-AG tissue levels without affecting the content of AEA, and led to increased anxiety-like behavior (312).…”

Section: Mood and Emotionsmentioning

confidence: 99%

“…FAAH inhibitors increasing AEA brain levels enhance the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus, thus eliciting antidepressant effects (295). Accordingly, 1) higher levels of FAAH in the rat frontal cortex and hippocampus may cause depressive-like disorders (885), and 2) chronic mild unpredictable stress, a model for depression, leads to impairment of 2-AG-mediated LTD in the CA1 region of the hippocampus, an effect prevented MAGL inhibition (942), which also enhances neurogenesis and LTP in the dentate gyrus (941). Accordingly, long-term antidepressant treatments increase 2-AG levels in different brain areas (803).…”

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

366

337

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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.

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“…159,160 Furthermore, the administration of 151 was demonstrated to produce gastroprotective and antidepressant-like effects post a 4 mg/kg intraperitoneal injection. 160,161 The determination of the binding mechanism indicated that 151 covalently and irreversibly bound to MAGL through the formation of the carbamylated-enzyme adduct ( Figure 56). intraperitoneal injection without resulting in cannabimimetic side effects including hypomotility, hypothermia and catalepsy.…”

Section: Carbamatesmentioning

confidence: 99%