Endocannabinoid Modulation of Predator Stress-Induced Long-Term Anxiety in Rats

Lim, Jinhwan; Igarashi, Miki; Jung, Kwang-Mook; Butini, Stefania; Campiani, Giuseppe; Piomelli, Daniele

doi:10.1038/npp.2015.284

Cited by 42 publications

(38 citation statements)

References 48 publications

(70 reference statements)

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“…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). These effects were also observed with the direct CB1 agonist CP55940.…”

Section: Discussionsupporting

confidence: 93%

“…Moreover, the anxiolytic effects of JZL184 were mediated by CB1 receptors as CB1 antagonist blocked these effects. Previous studies have provided mixed results in this regard; while Busques-Garcia found the anxiolytic effects of MAGL inhibition were mediated by CB2 (28) but not CB1 receptors, Lim et al , Morena et al , Sciolino et al , and the present results clearly indicate a CB1-mediated mechanism (29, 30, 43). …”

Section: Discussioncontrasting

confidence: 43%

“…Stress exposure can increase levels of 2-AG [(30, 33, 45–47) and current data], which are positively correlated with anxiety-like behaviors (43) and amygdala corticosterone levels (current data). Our data indicate that 2-AG augmentation reduces stress-induced anxiety-like behaviors suggest that physiological stress-induced increases in 2-AG represent a compensatory response aimed at counteracting stress-induced anxiety-like behaviors (albeit in an incomplete manner), and that pharmacological 2-AG augmentation bolsters this physiological response to more efficiently counteract the adverse effects of stress.…”

Section: Discussionmentioning

confidence: 69%

“…Consistent with these findings, we and others recently showed that genetic deficiency in 2-AG signaling is sufficient to induce anxious and depressive-like behavioral states (26, 27). Similarly, recent studies have demonstrated that augmenting 2-AG signaling can reduce anxiety-like behaviors (28–30). Despite these data a central question remains as to whether these two canonical eCB signaling systems, AEA and 2-AG, exhibit redundancy in their effect on anxiety-like behaviors, and if anxiety-related phenotypes associated with deficiencies in one system can be compensated for by augmentation of the other.…”

Section: Introductionmentioning

confidence: 86%

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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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Section: Discussionsupporting

confidence: 93%

Section: Discussioncontrasting

confidence: 43%

Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 86%

See 2 more Smart Citations

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

Bedse

Hartley

Neale

et al. 2017

Biological Psychiatry

102

View full text Add to dashboard Cite

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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%

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

Ligresti¹,

Petrocellis²,

Marzo³

2016

Physiological Reviews

365

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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Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain

et al. 2018

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The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as a therapeutic target. Inhibition of EC metabolizing enzymes elicits indirect agonism of cannabinoid receptors (CBRs) and therapeutic efficacy devoid of psychotropic effects. Based on our previous ligands, and aiming at the discovery of new selective FAAH inhibitors, we developed a series of 12 new compounds characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on monoacylglycerol lipase (MAGL) and CBRs. The most potent FAAH inhibitors of the newly developed series, 6-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-6-phenylhexylcarbamate (5 h) and 4-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-(6-phenylhexyl)carbamate (5 i) (nanomolar FAAH inhibitors, the latter of which also shows micromolar affinity at the CB R), were selected for further studies. Results of cell-based studies on a neuroblastoma cell line (IMR32) demonstrated 5 h, 5 i, and our reference compound 3 ([3-(3-carbamoylpyrrol-1-yl)phenyl] N-(5-phenylpentyl)carbamate) to lack any cytotoxic effect, while all three showed the ability to decrease oxidative stress by reducing the expression of the redox-sensitive transcription factor NF-κB. Encouraged by these data, these compounds were studied in vivo and were dosed orally in a mouse model of neuropathic pain. At 10 mg kg all the compounds were able to relieve the hypersensitivity induced by oxaliplatin.

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Endocannabinoid Modulation of Predator Stress-Induced Long-Term Anxiety in Rats

Cited by 42 publications

References 48 publications

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

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

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

Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain

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