The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

Fowler, Christopher J.

doi:10.1007/978-3-319-20825-1_4

Cited by 39 publications

(23 citation statements)

References 163 publications

(133 reference statements)

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“…(7) for a review). Because of its critical role in adjusting AEA concentrations (8–11), FAAH has been the topic of a growing number of investigation and drug development (12–15) and is being actively investigated as a therapeutic target for CUD (16–18). …”

Section: Introductionmentioning

confidence: 99%

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

Boileau

Mansouri

Williams

et al. 2016

Biological Psychiatry

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Background One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH) and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown. Methods Brain FAAH binding was measured with positron emission tomography and [11C]CURB in 22 healthy control subjects and ten chronic, frequent cannabis users during early abstinence. The FAAH genetic polymorphism (rs324420) and blood, urine and hair levels of cannabinoids and metabolites were determined. Results In cannabis users FAAH binding was significantly lower by 14–20% across the brain regions examined as compared to matched control subjects (overall Cohen’s d=0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness. Conclusions Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use.

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Section: Introductionmentioning

confidence: 99%

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

Boileau

Mansouri

Williams

et al. 2016

Biological Psychiatry

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“…To elucidate the neurobiological properties of other elements belonging to the endocannabinoid system, such as anandamide's major metabolic enzyme Fatty Acid Amide Hydrolase (FAAH), several studies have been aimed to describe the effects of FAAH in multiple experimental paradigms (Chauvet et al, 2015;Fowler, 2015;Panlilio et al, 2016), including experiments in sleep. For instance, FAAH-KO mice display no significant differences in sleep rebound after prolonged waking sessions (Huitro´n-Rese´ndiz et al, 2004) whereas studies outline that levels of expression of FAAH are lower in the brain after sleep deprivation in naı¨ve animals (Wang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis

et al. 2016

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Abstract-The endocannabinoid system comprises receptors (CB 1 and CB 2 cannabinoid receptors), enzymes (Fatty Acid Amide Hydrolase [FAAH], which synthesizes the endocannabinoid anandamide), as well as the anandamide membrane transporter (AMT). Importantly, previous experiments have demonstrated that the endocannabinoid system modulates multiple neurobiological functions, including sleep. For instance, SR141716A (the CB 1 cannabinoid receptor antagonist) as well as URB597 (the FAAH inhibitor) increase waking in rats whereas VDM-11 (the blocker of the AMT) enhances sleep in rodents. However, no further evidence is available regarding the neurobiological role of the endocannabinoid system in the homeostatic control of sleep. Therefore, the aim of the current experiment was to test if SR141716A, URB597 or VDM-11 would modulate the sleep rebound after sleep deprivation. Thus, these compounds were systemically injected (5, 10, 20 mg/kg; ip; separately each one) into rats after prolonged waking. We found that SR141716A and URB597 blocked in dose-dependent fashion the sleep rebound whereas animals treated with VDM-11 displayed sleep rebound during the recovery period. Complementary, injection after sleep deprivation of either SR141716A or URB597 enhanced dose-dependently the extracellular levels of dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT), as well as adenosine (AD) while VDM-11 caused a decline in contents of these molecules. These findings suggest that SR141716A or URB597 behave as a potent stimulants since they suppressed the sleep recovery period after prolonged waking. It can be concluded that elements of the endocannabinoid system, such as the CB 1 cannabinoid receptor, FAAH and AMT, modulate the sleep homeostasis after prolonged waking. Ó

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“…Drugs targeting the FAAH enzyme have been extensively studied for the treatment of endocannabinoids-related disorders, such as anxiety, depression, inflammation or neuropathic pain [72]. However, pharmaceutics are struggling to find a compound with high efficiency and low side effects, which may be due to chronic effects of FAAH inhibition that differ from acute effects [73,74] (Figure 2). …”

Section: Aea Metabolismmentioning

confidence: 99%

Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases

Bosch‐Bouju¹,

Layé²

2016

Cannabinoids in Health and Disease

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Omega-3 (ω-3) and omega-6 (ω-6) are polyunsaturated fatty acids (PUFAs) that play critical role in human health and have to be provided by food. In the brain, PUFAs are also precursors of endocannabinoids. The aim of this chapter is to review the existing literature on how dietary PUFAs impact on the endocannabinoid system in the brain and what are the consequences for brain function and dysfunction. In this chapter, we will first describe how PUFAs enter the brain, what are their metabolism processes and roles in brain function. We will describe the pathways from PUFAs to endocannabinoid production. Then, we will review the literature on how dietary ω-6/ω-3 ratio impacts the endocannabinoid system, in terms of endocannabinoid levels, proteins and endocannabinoid-dependent synaptic plasticity. In the next part, we will describe what we know about the interactions between PUFAs and endocannabinoids in neurological and neuropsychiatric disorders. Finally, we will conclude on the possible implications of the interactions between dietary PUFAs and endocannabinoids in the normal and pathological brain. In particular, we will discuss how dietary PUFAs, as homeostatic regulators of endocannabinoids, can constitute interesting therapeutic strategies for the prevention and/or treatment of neurological disorders with endocannabinoids impairment.

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The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

Cited by 39 publications

References 163 publications

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis

Dietary Omega-6/Omega-3 and Endocannabinoids: Implications for Brain Health and Diseases

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