Genetic Dissection of the Role of Cannabinoid Type-1 Receptors in the Emotional Consequences of Repeated Social Stress in Mice

Dubreucq, Sarah; Matías, Isabelle; Cardinal, Pierre; Häring, Martin; Lutz, Beat; Marsicano, Giovanni; Chaouloff, Francis

doi:10.1038/npp.2012.36

Cited by 133 publications

(131 citation statements)

References 97 publications

(157 reference statements)

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“…On the contrary, CUS mice showed reduced increase in 2-AG by JZL184, no combo-induced synergism, and consequently, no drug-induced anxiogenic and depression-like effects as seen in controls. This leads to the speculation that the druginduced exacerbation/over-activation of the 2-AG signaling, supposedly occurring in the control mice, does not happen in the CUS mice, because their 2-AG signaling is already perturbated by chronic stress exposure (Gorzalka et al, 2008;Dubreucq et al, 2012). Further investigations must be pursued to elucidate the mechanisms underlying these drug-induced effects.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

Lomazzo

Bîndilă

Remmers

et al. 2014

Neuropsychopharmacol

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125

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The occurrence of chronic stress, depression, and anxiety can increase nociception in humans and may facilitate the transition from localized to chronic widespread pain. The mechanisms underlying chronic widespread pain are still unknown, hindering the development of effective pharmacological therapies. Here, we exposed C57BL/6J mice to chronic unpredictable stress (CUS) to investigate how persistent stress affects nociception. Next, mice were treated with multiple intramuscular nerve growth factor (NGF) injections, which induced chronic widespread nociception. Thus, combination of CUS and NGF served as a model where psychophysiological impairment coexists with long-lasting hyperalgesia. We found that CUS increased anxiety-and depression-like behavior and enhanced basal nociception in mice. When co-applied with repeated NGF injections, CUS elicited a sustained long-lasting widespread hyperalgesia. In order to evaluate a potential therapeutic strategy for the treatment of chronic pain associated with stress, we hypothesized that the endocannabinoid system (ECS) may represent a target signaling system. We found that URB597, an inhibitor of the anandamidedegrading enzyme fatty acid amide hydrolase (FAAH), and JZL184, an inhibitor of the 2-arachidonoyl glycerol-degrading enzyme monoacylglycerol lipase (MAGL), increased eCB levels in the brain and periphery and were both effective in reducing CUS-induced anxiety measured by the light-dark test and CUS-induced thermal hyperalgesia. Remarkably, the long-lasting widespread hyperalgesia induced by combining CUS and NGF was effectively reduced by URB597, but not by JZL184. Simultaneous inhibition of FAAH and MAGL did not improve the overall therapeutic response. Therefore, our findings indicate that enhancement of anandamide signaling with URB597 is a promising pharmacological approach for the alleviation of chronic widespread nociception in stress-exposed mice, and thus, it could represent a potential treatment strategy for chronic pain associated with neuropsychiatric disorders in humans.

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Section: Discussionmentioning

confidence: 99%

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

Lomazzo

Bîndilă

Remmers

et al. 2014

Neuropsychopharmacol

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125

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“…Within the amygdala, this effect appears to be quite prominent as exposure of both rats and mice to restraint stress causes a reduction in the tissue levels of AEA (Gray et al, 2015;Hill et al, 2009c;Patel et al, 2005b;Rademacher et al, 2008). Similarly, both acute restraint stress and social defeat stress have been found to reduce AEA content within the hippocampus (Dubreucq et al, 2012;Wang et al, 2012b). This reduction in AEA content is, at least in part, mediated by an increase in AEA hydrolysis by FAAH as acute stress increases FAAH activity within the amygdala (Gray et al, 2015;Hill et al, 2009c).…”

Section: Effects Of Acute Stress On Aea Brain Levelsmentioning

confidence: 96%

“…Interestingly, this effect appears to be conserved throughout the lifespan as early life stress in the form of maternal separation has also been shown to reduce AEA content within the hippocampus (Marco et al, 2013). Unlike the consistency seen in the amygdala and hippocampus, the mPFC seems to be somewhat of a more complex structure as exposure to swim stress has been found to produce a robust reduction of AEA content (McLaughlin et al, 2012), but neither acute restraint (Gray et al, 2015;Hill et al, 2011b;Rademacher et al, 2008) nor acute social defeat (Dubreucq et al, 2012) were found to have any effect on AEA content in the mPFC. Similarly, restraint stress was found to have no effect on FAAH mRNA, protein, or activity within the mPFC (Gray et al, 2015;Navarria et al, 2014).…”

Section: Effects Of Acute Stress On Aea Brain Levelsmentioning

confidence: 99%

Neurobiological Interactions Between Stress and the Endocannabinoid System

Morena

Patel

Bains

et al. 2015

Neuropsychopharmacol

510

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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“…WT and TPH2-CB 1 -KO littermates (19), in which the CB 1 gene is deleted in the raphe nucleus but not in other brain regions (Fig. 1C and Fig.…”

Section: Cb 1 Receptors In Different Brain Neuron Types Are Dispensabmentioning

confidence: 99%

Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB ₁ receptor blockade

Bellocchio

Soria-Gómez

Quarta

et al. 2013

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

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110

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Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB 1 ) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB 1 receptor blockade, we combined the acute injection of the CB 1 receptor antagonist rimonabant with the use of conditional CB 1 -knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB 1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB 1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrientspecific component acutely regulated by CB 1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB 1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB 1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB 1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.fear and anxiety | sympathetic system

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Genetic Dissection of the Role of Cannabinoid Type-1 Receptors in the Emotional Consequences of Repeated Social Stress in Mice

Cited by 133 publications

References 97 publications

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

Neurobiological Interactions Between Stress and the Endocannabinoid System

Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB ₁ receptor blockade

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Genetic Dissection of the Role of Cannabinoid Type-1 Receptors in the Emotional Consequences of Repeated Social Stress in Mice

Cited by 133 publications

References 97 publications

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

Therapeutic Potential of Inhibitors of Endocannabinoid Degradation for the Treatment of Stress-Related Hyperalgesia in an Animal Model of Chronic Pain

Neurobiological Interactions Between Stress and the Endocannabinoid System

Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB 1 receptor blockade

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Resources

About

Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB ₁ receptor blockade