Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia

Lichtman, Aron H.; Shelton, Christopher C.; Advani, Tushar; Cravatt, Benjamin F.

doi:10.1016/j.pain.2004.01.022

Cited by 277 publications

(258 citation statements)

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“…Doses of JZL184 (20 and 40 mg/kg) and JZL195 (20 mg/ kg) were based on their efficacy in elevating brain levels of endocannabinoids, while the doses of THC and rimonabant were selected based on their respective ability to impair spatial memory and antagonize cannabinoid-induced memory deficits, respectively. 11,18,19,23 Procedures. Morris Water Maze.…”

Section: ■ Methodsmentioning

confidence: 99%

Dual Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Blockade Produces THC-Like Morris Water Maze Deficits in Mice

Wise

Long

Abdullah

et al. 2012

ACS Chem. Neurosci.

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Acute administration of Δ 9 -tetrahydrocannabinol (THC) or exposure to marijuana smoke impairs short-term spatial memory in water maze tasks through a CB 1 receptor mechanism of action. N-Arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) are endogenous cannabinoids that are predominantly metabolized by the respective enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Although the MAGL inhibitor JZL184 enhances short-term synaptic plasticity, it has yet to be evaluated in the Morris water maze. Previous research demonstrated that simultaneous, complete blockade of FAAH and MAGL produces full blown THC-like effects. Thus, in the following studies we tested whether dual blockade of FAAH and MAGL would impair learning in a repeated acquisition Morris water maze task. Mice treated with the dual FAAH/MAGL inhibitor JZL195 (20 mg/kg) as well as JZL184-treated FAAH −/− mice displayed robust deficits in Morris water maze performance that were similar in magnitude to THC-treated mice. While 20 or 40 mg/kg impaired water maze performance in FAAH −/− mice, only the high dose of JZL184 disrupted performance in FAAH +/+ mice. The memory impairing effects of JZL184 were blocked by the CB 1 receptor antagonist rimonabant. Neither JZL184 nor JZL195 impaired performance in a cued version of the water maze task, arguing against the notion that sensorimotor or motivational deficits accounted for the impaired acquisition performance. JZL184 increased 2-AG levels in the hippocampus, prefrontal cortex, and cerebellum to a similar degree in FAAH −/− and +/+ mice. FAAH −/− mice, regardless of drug treatment, possessed elevated AEA levels in each brain region assessed. The results of this study reveal that concomitant increases in AEA and 2-AG disrupt short-term spatial memory performance in a manner similar to that of THC. KEYWORDS: Cannabinoid, memory, N-arachidonoylethanolamine (anandamide), 2-arachidonoylglycerol (2-AG), fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL)The endogenous cannabinoid signaling system has been widely studied to understand its role in physiological and pathological processes. To date, two major endogenous cannabinoids, Narachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), and their distinct biosynthetic and degradative pathways have been extensively investigated. Both AEA and 2-AG are synthesized and released on demand, in response to diverse physiological stimuli, and are rapidly inactivated by hydrolysis after cellular reuptake. AEA 1 is metabolized by fatty acid amide hydrolase (FAAH), whereas monoacylglycerol lipase (MAGL) is the major catabolic enzyme of 2-AG. 2 These endogenous cannabinoids as well as exogenously administered cannabinoids activate two cannabinoid receptors, CB 1 and CB 2 . 3,4 CB 1 receptors are heterogeneously distributed in high concentrations throughout the central nervous system and periphery and are the predominant target for the psychomimetic effects of Δ 9 -tetrahydrocannabi...

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Section: ■ Methodsmentioning

confidence: 99%

Dual Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Blockade Produces THC-Like Morris Water Maze Deficits in Mice

Wise

Long

Abdullah

et al. 2012

ACS Chem. Neurosci.

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“…Accordingly, FAAH (À/À) mice represent a useful tool to evaluate the physiological function of these lipid signaling molecules (Cravatt et al, 2001;Clement et al, 2003). In addition to displaying dramatically enhanced responses to intraperitoneal injections of anandamide, FAAH (À/À) mice display CB 1 receptor mediated hypoalgesic responses to radiant heat and inflammatory stimuli (Cravatt et al, 2001;Lichtman et al, 2004b). In parallel with the transgenic models, several pharmacological inhibitors of FAAH have been developed and shown to elicit cannabinoid-receptor mediated analgesia, notably reversible a-ketoheterocyle inhibitors (eg, OL-135), and irreversible carbamate inhibitors (eg, URB-597).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task

Varvel

Wise

Niyuhire

et al. 2006

Neuropsychopharmacol

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Recent reports have demonstrated that disruption of CB 1 receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (À/À) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAHcompromised mice also exhibited a significant increase in acquisition rate. The CB 1 receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB 1 receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, D 9 -tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB 1 receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder.

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“…A similar pattern of phenotypes is observed in FAAH−/− mice. 8,11 Selective MAGL inhibitors, such as the carbamate JZL184, have only recently been developed 21,22 and are therefore less well-studied, but appear to produce a broader array of cannabinoid effects in rodents that nonetheless still avoid the psychotropic activity of direct CB1 agonists. 23 Complete pharmacologic or genetic blockade of MAGL for extended periods of time also leads to behavioral tolerance and desensitization of brain CB1 receptors, 24 but these adaptations can be avoided with lower doses of JZL184 that produce chronic, partial inhibition of MAGL.…”

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confidence: 99%

O-Hydroxyacetamide Carbamates as a Highly Potent and Selective Class of Endocannabinoid Hydrolase Inhibitors

Niphakis

Johnson

Ballard

et al. 2011

ACS Chem. Neurosci.

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The two major endocannabinoid transmitters, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are degraded by distinct enzymes in the nervous system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. FAAH and MAGL inhibitors cause elevations in brain AEA and 2-AG levels, respectively, and reduce pain, anxiety, and depression in rodents without causing the full spectrum of psychotropic behavioral effects observed with direct cannabinoid receptor-1 (CB1) agonists. These findings have inspired the development of several classes of endocannabinoid hydrolase inhibitors, most of which have been optimized to show specificity for either FAAH or MAGL or, in certain cases, equipotent activity for both enzymes. Here, we investigate an unusual class of Ohydroxyacetamide carbamate inhibitors and find that individual compounds from this class can serve as selective FAAH or dual FAAH/MAGL inhibitors in vivo across a dose range (0.125−12.5 mg kg ) suitable for behavioral studies. Competitive and click chemistry activity-based protein profiling confirmed that the O-hydroxyacetamide carbamate SA-57 is remarkably selective for FAAH and MAGL in vivo, targeting only one other enzyme in brain, the additional 2-AG hydrolase ABHD6. These data designate O-hydroxyacetamide carbamates as a versatile chemotype for creating endocannabinoid hydrolase inhibitors that display excellent in vivo activity and tunable selectivity for FAAH-anandamide versus MAGL (and ABHD6)-2-AG pathways.

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Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia

Cited by 277 publications

References 44 publications

Dual Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Blockade Produces THC-Like Morris Water Maze Deficits in Mice

Dual Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Blockade Produces THC-Like Morris Water Maze Deficits in Mice

Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task

O-Hydroxyacetamide Carbamates as a Highly Potent and Selective Class of Endocannabinoid Hydrolase Inhibitors

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