Antidepressant-like activity and cardioprotective effects of fatty acid amide hydrolase inhibitor URB694 in socially stressed Wistar Kyoto rats

Carnevali, Luca; Vacondio, Federica; Rossi, Stefano; Callegari, Sergio; Macchi, Emilio; Spadoni, Gilberto; Bedini, Annalida; Rivara, Silvia; Mor, Marco; Sgoifo, Andrea

doi:10.1016/j.euroneuro.2015.07.015

Cited by 29 publications

(11 citation statements)

References 58 publications

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“…While it cannot be excluded that at least part of the mechanisms underlying the antidepressant-like effects of FAAH inhibitors overlap with those responsible for their anxiolytic-like effects 13 , 87 , several authors have highlighted the importance of AEA signaling at CB1 receptors in the prefrontal cortex and the hippocampus in these effects. It was notably proposed that the downstream mechanisms of FAAH inhibitors converge with those of 5-HT-acting antidepressants, including modifications of hippocampal 5-HT receptor function, and enhancement in BDNF production in the hippocampus and prefrontal cortex 87 , 91 .…”

Section: Discussionmentioning

confidence: 99%

The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents

Griebel

Stemmelin

Lopez-Grancha

et al. 2018

Sci Rep

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Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.

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Section: Discussionmentioning

confidence: 99%

The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents

Griebel

Stemmelin

Lopez-Grancha

et al. 2018

Sci Rep

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“…Despite the absence of changes in baseline HR, some models induce profound changes in cardiac function. For example, repeated social defeat episodes caused accumulation of fibrous tissue in the left ventricular myocardium, maladaptive cardiac hypertrophy, changes in electrical conduction system of the heart (e.g., reduced myocardial refractoriness and impaired conduction), and increased susceptibility to cardiac arrhythmias (Gelsema et al, 1994 ; Costoli et al, 2004 ; Carnevali et al, 2013b , 2015 ; Sgoifo et al, 2014 ). Disruption of the circadian rhythm for HR has also been reported following repeated exposure to social defeat (Tornatzky and Miczek, 1993 ; Sgoifo et al, 2002 ; Carnevali et al, 2015 ).…”

Section: Cardiovascular Responses To Stress: Influence Of Chronicitymentioning

confidence: 99%

“…This finding is in line with the increase in baseline HR observed in Sprague–Dawley rats following repeated exposure to social defeat (Sévoz-Couche et al, 2013 ). However, Sprague–Dawley rats seem to be selectively susceptible to resting tachycardia induced by repeated social defeat once studies did not identify changes in baseline HR in either mice (Bartolomucci et al, 2003 ; Costoli et al, 2004 ; Carnevali et al, 2012 ) or wide-type Groningen (Sgoifo et al, 2001 ; Carnevali et al, 2013b ), Long-Evans (Tornatzky and Miczek, 1993 ), Wistar-Kyoto (Carnevali et al, 2015 ), Lister hooded (Chung et al, 1999 ), and Dahl-s (Adams and Blizard, 1986 ; Adams et al, 1987 ) rats. Nevertheless, differences in experimental protocol may also account for the differences in findings of autonomic/cardiovascular changes because exposures to social defeat in different studies ranged from 5 to 25 days (Table 2 ).…”

Section: Cardiovascular Responses To Stress: Influence Of Chronicitymentioning

confidence: 99%

Emotional Stress and Cardiovascular Complications in Animal Models: A Review of the Influence of Stress Type

Crestani

2016

Front. Physiol.

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Emotional stress has been recognized as a modifiable risk factor for cardiovascular diseases. The impact of stress on physiological and psychological processes is determined by characteristics of the stress stimulus. For example, distinct responses are induced by acute vs. chronic aversive stimuli. Additionally, the magnitude of stress responses has been reported to be inversely related to the degree of predictability of the aversive stimulus. Therefore, the purpose of the present review was to discuss experimental research in animal models describing the influence of stressor stimulus characteristics, such as chronicity and predictability, in cardiovascular dysfunctions induced by emotional stress. Regarding chronicity, the importance of cardiovascular and autonomic adjustments during acute stress sessions and cardiovascular consequences of frequent stress response activation during repeated exposure to aversive threats (i.e., chronic stress) is discussed. Evidence of the cardiovascular and autonomic changes induced by chronic stressors involving daily exposure to the same stressor (predictable) vs. different stressors (unpredictable) is reviewed and discussed in terms of the impact of predictability in cardiovascular dysfunctions induced by stress.

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“…Specifically, the relatively deficient eCB function is associated with increased anxiety and depression, and as such, impaired eCB activity may contribute to the negative affective states and increased stress responsivity that underlie negative reinforcement mechanisms driving alcohol drinking by dependent individuals and that contribute to alcohol relapse following periods of abstinence [Parsons & Hurd, 2015]. Pharmacologic and genetic manipulations (knockout or knock-in) of FAAH have been implicated in anxiolytic and anti-depressive behaviors [Bortolato et al 2007; Gunduz-Cinar et al 2013; Kathuria et al 2003; Moreira et al 2008; Carnevali et al 2015]. However, there is no study on FAAH inhibitors in rodent models with alcohol withdrawal from high intake, though FAAH inhibition decreases anxiety-like behaviors that are present during alcohol withdrawal [Cippitelli et al 2008].…”

Section: Introductionmentioning

confidence: 99%

Blockade of alcohol escalation and “relapse” drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice

et al. 2017

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Background Anandamide (AEA)-dependent signaling is regulated by the catabolic enzyme fatty acid amide hydrolase (FAAH). Several lines of evidence have demonstrated that FAAH and AEA are involved in the behavioral effects of alcohol. Therefore, we investigated whether a selective FAAH inhibitor, URB597 (Cyclohexylcarbamic acid 3′-[aminocarbonyl]-[1,1′-biphenyl]-3-yl ester), altered alcohol intake in mice in a voluntary alcohol drinking model. Methods Mice, subjected to 3 weeks of chronic intermittent access (IA) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference. We evaluated the pharmacological effects of URB597 after both acute (1-day) withdrawal from chronic IA and 1-week withdrawal using the alcohol deprivation effect (ADE) model. AEA and N-acyl ethanolamide (NAE) abundances were determined after chronic IA, acute (1-day) or long-term (1 and 2 weeks) withdrawal in four brain regions. Results Acute pretreatment with URB597 reduced alcohol intake and preference after acute withdrawal. This effect was blocked by pretreatment with a selective type 1 cannabinoid receptor (CB1) antagonist, suggesting a CB1-mediated mechanism. Both single- and multiple- dosing regimens with an effective dose of URB597 prevented the ADE, with no tolerance development after the multi-dosing regimen. AEA and NAE levels were transiently increased in all brain regions measured after acute withdrawal, indicating that the endocannabinoid system is involved in acute alcohol withdrawal stress response. Conclusion FAAH inhibitors reduce alcohol escalation and “relapse” drinking in mice.

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Antidepressant-like activity and cardioprotective effects of fatty acid amide hydrolase inhibitor URB694 in socially stressed Wistar Kyoto rats

Cited by 29 publications

References 58 publications

The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents

The selective reversible FAAH inhibitor, SSR411298, restores the development of maladaptive behaviors to acute and chronic stress in rodents

Emotional Stress and Cardiovascular Complications in Animal Models: A Review of the Influence of Stress Type

Blockade of alcohol escalation and “relapse” drinking by pharmacological FAAH inhibition in male and female C57BL/6J mice

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