Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

Ogasawara, Daisuke; Deng, Hui; Viader, Andreu; Baggelaar, Marc P.; Breman, Arjen C.; Dulk, Hans den; Nieuwendijk, Adrianus M. C. H. van den; Soethoudt, Marjolein; Wel, Tom van der; Zhou, Juan; Overkleeft, Herman S.; Sanchez‐Alavez, Manuel; Mori, Simone; Nguyen, William; Conti, Bruno; Liu, Xiaojie; Chen, Yao; Liu, Qingsong; Cravatt, Benjamin F.; Stelt, Mario van der

doi:10.1073/pnas.1522364112

Cited by 121 publications

(204 citation statements)

References 66 publications

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“…37), which selectively reduces brain 2-AG and AA but not AEA levels (Fig. 5a–c), would increase susceptibility to stress-induced anxiety-like behaviour.…”

Section: Resultsmentioning

confidence: 99%

Endocannabinoid signalling modulates susceptibility to traumatic stress exposure

et al. 2017

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Stress is a ubiquitous risk factor for the exacerbation and development of affective disorders including major depression and posttraumatic stress disorder. Understanding the neurobiological mechanisms conferring resilience to the adverse consequences of stress could have broad implications for the treatment and prevention of mood and anxiety disorders. We utilize laboratory mice and their innate inter-individual differences in stress-susceptibility to demonstrate a critical role for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) in stress-resilience. Specifically, systemic 2-AG augmentation is associated with a stress-resilient phenotype and enhances resilience in previously susceptible mice, while systemic 2-AG depletion or CB1 receptor blockade increases susceptibility in previously resilient mice. Moreover, stress-resilience is associated with increased phasic 2-AG-mediated synaptic suppression at ventral hippocampal-amygdala glutamatergic synapses and amygdala-specific 2-AG depletion impairs successful adaptation to repeated stress. These data indicate amygdala 2-AG signalling mechanisms promote resilience to adverse effects of acute traumatic stress and facilitate adaptation to repeated stress exposure.

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“…37), which selectively reduces brain 2-AG and AA but not AEA levels (Fig. 5a–c), would increase susceptibility to stress-induced anxiety-like behaviour.…”

Section: Resultsmentioning

confidence: 99%

Endocannabinoid signalling modulates susceptibility to traumatic stress exposure

et al. 2017

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“…However, whether pharmacological AEA augmentation can reciprocally compensate for anxiety states induced by selective 2-AG depletion is not known. To explicitly test this hypothesis, we used irreversible DAGL inhibitor DO34 (50 mg kg −1 ) to block endogenous synthesis of 2-AG (40), either alone or in combination with the PF-3845 (1 mg kg −1 ). To validate our pharmacological treatments, we analyzed the effects of DO34 and DO34+PF-3845 on brain eCB levels.…”

Section: Resultsmentioning

confidence: 99%

“…resulted in rapid and dramatic reductions in 2-AG and AA compared to vehicle-treated mice (Fig. 5A–B) (40); however, AEA levels were unaffected (Fig. 5C).…”

Section: Resultsmentioning

confidence: 99%

“…First, facilitating 2-AG signaling through inhibition of 2-AG degrading enzyme, MAGL (34), and second, impairing 2-AG signaling by pharmacological blockade of the 2-AG synthesizing enzyme, DAGL (40). Consistent with previous reports, our results demonstrated that facilitation of 2-AG signaling not only reduced anxiety-like behaviors at basal conditions (28, 29, 41–43), but also reduced stress-induced anxiety-like behaviors (30, 44).…”

Section: Discussionmentioning

confidence: 99%

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Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety

Bedse

Hartley

Neale

et al. 2017

Biological Psychiatry

102

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Background Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood. Methods We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety, and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice. Results Selective 2-AG augmentation reduced anxiety in the light-dark box assay, and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct CB1 receptor stimulation with tetrahydrocannabinol (THC). Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation. Conclusions Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than previously appreciated.

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“…Cravatt's Inaugural Article (9) investigates the function of enzymes called diacylglycerol lipases (DAGLs), which regulate the production of endocannabinoids. Understanding the full spectrum of functions for DAGL-endocannabinoid pathways, however, requires selective inhibitors to perturb these pathways in cell and animal models.…”

Section: Endocannabinoid-regulating Enzymesmentioning

confidence: 99%

Profile of Benjamin Cravatt

Viegas¹

2016

Proc. Natl. Acad. Sci. U.S.A.

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Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

Cited by 121 publications

References 66 publications

Endocannabinoid signalling modulates susceptibility to traumatic stress exposure

Endocannabinoid signalling modulates susceptibility to traumatic stress exposure

Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety

Profile of Benjamin Cravatt

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