Benjamin F Cravatt

The Scripps Research Institute, لا هویا, California, United States

Are you Benjamin F Cravatt?

Claim your profile

Publications (441)3534.84 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception, but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to CB1 receptor functional tolerance, which represents another challenge in this potential therapeutic strategy. Therefore, the present study tested whether full FAAH inhibition, combined with partial MAGL inhibition, would produce sustained antinociceptive effects with minimal cannabimimetic side effects. Accordingly, we tested a high dose of the FAAH inhibitor PF-3845 (10 mg/kg) given in combination with a low dose of the MAGL inhibitor JZL184 (4 mg/kg) in mouse models of inflammatory and neuropathic pain. This combination of inhibitors elicited profound increases in brain AEA levels (>10-fold), but only 2-3 fold increases in brain 2-AG levels. Importantly, this combination produced significantly greater antinociceptive effects than single enzyme inhibition and did not elicit common cannabimimetic effects (e.g., catalepsy, hypomotility, hypothermia, and substitution for THC in the drug discrimination assay), although these side effects emerged with high dose JZL184 (i.e., 100 mg/kg). Finally, repeated administration of this combination did not lead to tolerance to its anti-allodynic actions in the carrageenan assay or CB1 receptor functional tolerance. Thus, full FAAH inhibition combined with partial MAGL inhibition reduces neuropathic and inflammatory pain states, with minimal cannabimimetic effects. The American Society for Pharmacology and Experimental Therapeutics.
    Journal of Pharmacology and Experimental Therapeutics 05/2015; DOI:10.1124/jpet.115.222851 · 3.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Targeting dysregulated metabolic pathways is a promising therapeutic strategy for eradicating cancer. Understanding how frequently altered oncogenes regulate metabolic enzyme targets would be useful in identifying both broad-spectrum and targeted metabolic therapies for cancer. Here, we used activity-based protein profiling to identify serine hydrolase activities that were consistently upregulated by various human oncogenes. Through this profiling effort, we found oncogenic regulatory mechanisms for several cancer-relevant serine hydrolases and discovered that platelet activating factor acetylhydrolase 1B2 and 1B3 (PAFAH1B2 and PAFAH1B3) activities were consistently upregulated by several oncogenes, alongside previously discovered cancer-relevant hydrolases fatty acid synthase and monoacylglycerol lipase. While we previously showed that PAFAH1B2 and 1B3 were important in breast cancer, our most recent profiling studies have revealed that these enzymes may be dysregulated broadly across many types of cancers. Here, we find that pharmacological blockade of both enzymes impairs cancer pathogenicity across multiple different types of cancer cells, including breast, ovarian, melanoma, and prostate cancer. We also show that pharmacological blockade of PAFAH1B2 and 1B3 causes unique changes in lipid metabolism, including heightened levels of tumor-suppressing lipids. Our results reveal oncogenic regulatory mechanisms of several cancer-relevant serine hydrolases using activity-based protein profiling, and we show that PAFAH1B2 and 1B3 are important in maintaining cancer pathogenicity across a wide spectrum of cancer types.
    ACS Chemical Biology 05/2015; DOI:10.1021/acschembio.5b00053 · 5.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anandamide (AEA) is an endocannabinoid (EC) that modulates multiple functions in the CNS and that is released in areas of injury, exerting putative neuroprotective actions. In the present study, we have used intravital microscopy to analyze the role of the EC system in the glial response against an acute insult. Our data show that AEA modulates astroglial function in vivo by increasing connexin-43 hemichannel (HC) activity. Furthermore, the genetic inactivation of the AEA-degrading enzyme, fatty acid amide hydrolase (FAAH), also increased HC activity and enhanced the microglial response against an acute injury to the brain parenchyma, effects that were mediated by cannabinoid CB1receptors. The contribution of ATP released through astrocytic HC was critical for the microglial response, as this was prevented by the use of the HC blocker flufenamic acid and by apyrase. As could be expected, brain concentrations of AEA, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were elevated in FAAH-null mice, while 2-arachidonoylglycerol (2-AG) concentrations remained unaltered. In summary, these findings demonstrate that AEA modifies glial functions by promoting an enhanced pro-inflammatory glial response in the brain. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 04/2015; DOI:10.1016/j.nbd.2015.04.005 · 5.20 Impact Factor
  • Hyeon-Cheol Lee, Gabriel M Simon, Benjamin F Cravatt
    [Show abstract] [Hide abstract]
    ABSTRACT: N-Acyl phospholipids are atypical components of cell membranes that bear three acyl chains and serve as potential biosynthetic precursors for lipid mediators such as endocannabinoids. Biochemical studies have implicated ABHD4 as a brain N-acyl phosphatidylethanolamine (NAPE) lipase, but in vivo evidence for this functional assignment is lacking. Here, we describe ABHD4(-/-) mice and their characterization using untargeted lipidomics to discover that ABHD4 regulates multiple classes of brain N-acyl phospholipids. In addition to showing reductions in brain glycerophospho-NAEs (GP-NAEs) and plasmalogen-based lyso-NAPEs (lyso-pNAPEs), ABHD4(-/-) mice exhibited decreases in a distinct set of brain lipids that were structurally characterized as N-acyl lysophosphatidylserines (lyso-NAPSs). Biochemical assays confirmed that NAPS lipids are direct substrates of ABHD4. These findings, taken together, designate ABHD4 as a principal regulator of N-acyl phospholipid metabolism in the mammalian nervous system.
    Biochemistry 04/2015; 54(15). DOI:10.1021/acs.biochem.5b00207 · 3.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) plays an important role in a variety of physiological processes, but its rapid breakdown by monoacylglycerol lipase (MAGL) results in short-lived actions. Initial MAGL inhibitors were limited by poor selectivity and low potency. Here, we tested JZL184 and MJN110, MAGL inhibitor that possesses increased selectivity and potency, in mouse behavioral assays of neuropathic pain (chronic constrictive injury of the sciatic nerve; CCI), interoceptive cannabimimetic effects (drug discrimination paradigm), and locomotor activity in an open field test. MJN110 (1.25 and 2.5 mg/kg) and JZL184 (16 and 40 mg/kg) significantly elevated 2-AG and decreased arachidonic acid, but did not affect anandamide (AEA) in whole brain. Both MAGL inhibitors significantly reduced CCI-induced mechanical allodynia with the following potencies [ED50 (95% CL) values in mg/kg: MJN110 (0.43 (0.30-0.63) > JZL184 (17.8 (11.6-27.4))], and also substituted for the potent cannabinoid receptor agonist CP55,940 in the drug discrimination paradigm [ED50 (95% CL) values in mg/kg: MJN110 (0.84 (0.69-1.02)) > JZL184 (24.9 (14.6-42.5))]. However, these compounds elicited differential effects on locomotor behavior. Similar to CB1 receptor agonists, JZL184 produced hypomotility, while MJN110 increased locomotor behavior and did not produce catalepsy or hypothermia. Although these results suggest that MAGL inhibitors hold promise for the treatment of neuropathic pain, their substitution for CP55,940 in the drug discrimination assay may not be desirable for a therapeutic drug. Nonetheless, in contrast to CB1 receptor agonists, each MAGL inhibitor tested elicited few or no pharmacological effects in other standard assays used to infer cannabimimetic activity. The American Society for Pharmacology and Experimental Therapeutics.
    Journal of Pharmacology and Experimental Therapeutics 03/2015; DOI:10.1124/jpet.114.222315 · 3.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cross-species studies enable rapid translational discovery and produce the broadest impact when both mechanism and phenotype are consistent across organisms. We developed a knock-in mouse that biologically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (FAAH) (C385A; rs324420), the primary catabolic enzyme for the endocannabinoid anandamide. This common polymorphism impacts the expression and activity of FAAH, thereby increasing anandamide levels. Here, we show that the genetic knock-in mouse and human variant allele carriers exhibit parallel alterations in biochemisty, neurocircuitry and behaviour. Specifically, there is reduced FAAH expression associated with the variant allele that selectively enhances fronto-amygdala connectivity and fear extinction learning, and decreases anxiety-like behaviours. These results suggest a gain of function in fear regulation and may indicate for whom and for what anxiety symptoms FAAH inhibitors or exposure-based therapies will be most efficacious, bridging an important translational gap between the mouse and human.
    Nature Communications 03/2015; 6:6395. DOI:10.1038/ncomms7395 · 10.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cannabinoid receptor agonists, such as Δ(9)-THC, the primary active constituent of Cannabis sativa, have anti-pyrogenic effects in a variety of assays. Recently, attention has turned to the endogenous cannabinoid system and how endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide, regulate multiple homeostatic processes, including thermoregulation. Inhibiting endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH), elevates levels of 2-AG or anandamide in vivo, respectively. The purpose of this experiment was to test the hypothesis that endocannabinoid catabolic enzymes function to maintain thermal homeostasis in response to hypothermic challenge. In separate experiments, male C57BL/6J mice were administered a MAGL or FAAH inhibitor, and then challenged with the bacterial endotoxin lipopolysaccharide (LPS; 2 mg/kg ip) or a cold (4 °C) ambient environment. Systemic LPS administration caused a significant decrease in core body temperature after 6 h, and this hypothermia persisted for at least 12 h. Similarly, cold environment induced mild hypothermia that resolved within 30 min. JZL184 exacerbated hypothermia induced by either LPS or cold challenge, both of which effects were blocked by rimonabant, but not SR144528, indicating a CB1 cannabinoid receptor mechanism of action. In contrast, the FAAH inhibitor, PF-3845, had no effect on either LPS-induced or cold-induced hypothermia. These data indicate that unlike direct acting cannabinoid receptor agonists, which elicit profound hypothermic responses on their own, neither MAGL nor FAAH inhibitors affect normal body temperature. However, these endocannabinoid catabolic enzymes play distinct roles in thermoregulation following hypothermic challenges.
    Journal of Neuroimmune Pharmacology 02/2015; DOI:10.1007/s11481-015-9593-1 · 3.17 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) inhibitors exert pre-clinical effects indicative of therapeutic potential (i.e., analgesia). However, the extent to which MAGL and FAAH inhibitors produce unwanted effects remains unclear. Here, FAAH and MAGL inhibition was examined separately and together in a Δ9-tetrahydrocannabinol (Δ9-THC; 5.6 mg/kg i.p.) discrimination assay predictive of subjective effects associated with cannabis use, and the relative contribution of N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) in the prefrontal cortex, hippocampus, and caudate putamen to those effects was examined. Δ9-THC dose-dependently increased Δ9-THC appropriate responses (ED50 value = 3.1 mg/kg), whereas the FAAH inhibitors PF-3845 and URB597 or a MAGL inhibitor JZL184 alone did not substitute for the Δ9-THC discriminative stimulus. The non-selective FAAH/MAGL inhibitors SA-57 and JZL195 fully substituted for Δ9-THC with ED50 values equal to 2.7 and 21.8 mg/kg, respectively. Full substitution for Δ9-THC also was produced by a combination of JZL184 and PF-3845, but not by a combination of JZL184 and URB597 (i.e., 52% maximum). The CB1 receptor antagonist rimonabant attenuated the discriminative stimulus effects of Δ9-THC, SA-57, JZL195, and the combined effects of JZL184 and PF-3845. Full substitution for the Δ9-THC discriminative stimulus occurred only when both 2-AG and AEA were significantly elevated, and the patterns of increased endocannabinoid content were similar among brain regions. Overall, these results suggest that increasing both endogenous 2-AG and AEA produces qualitatively unique effects (i.e., the subjective effects of cannabis) that are not obtained from increasing either 2-AG or AEA separately. The American Society for Pharmacology and Experimental Therapeutics.
    Journal of Pharmacology and Experimental Therapeutics 02/2015; 353(2). DOI:10.1124/jpet.115.222836 · 3.86 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: The discovery of enzyme inhibitors relies on synthetic methods that enable rapid and modular construction of small molecules. Heterocyclic fragments designed to maximize enthalpic interactions with their protein targets represent a particularly desirable class of molecules. Here we describe a reagent that enables straightforward construction of "borofragments", in which a heterocycle is separated from the boron center by two or three rotatable bonds. The stability of these molecules depends on the MIDA group which likely acts as a slow-release element under biological conditions. Borofragments can be used to discover inhibitors of enzymes that use catalytic oxygen nucleophiles. We have employed this method to identify inhibitors of ABHD10 and the predicted carboxypeptidase CPVL. This technique should be applicable to other classes of targets.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Platelet-activating factor acetylhydrolases (PAFAHs) 1b2 and 1b3 are poorly characterized serine hydrolases that form a complex with a noncatalytic protein (1b1) to regulate brain development, spermatogenesis, and cancer pathogenesis. Determining physiological substrates and biochemical functions for the PAFAH1b complex would benefit from selective chemical probes that can perturb its activity in living systems. Here, we report a class of tetrahydropyridine reversible inhibitors of PAFAH1b2/3 discovered using a fluorescence polarization-activity-based protein profiling (fluopol-ABPP) screen of the NIH 300 000+ compound library. The most potent of these agents, P11, exhibited IC50 values of ∼40 and 900 nM for PAFAH1b2 and 1b3, respectively. We confirm selective inhibition of PAFAH1b2/3 in cancer cells by P11 using an ABPP protocol adapted for in situ analysis of reversible inhibitors and show that this compound impairs tumor cell survival, supporting a role for PAFAH1b2/3 in cancer.
    ACS Chemical Biology 01/2015; 10(4). DOI:10.1021/cb500893q · 5.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: β-Lactones are a privileged structural motif as enzyme inhibitors and chemical probes, particularly for the inhibition of enzymes from the serine hydrolase class. Herein, we demonstrate that cross-metathesis (CM) of α-methylene-β-lactones offers rapid access to structurally diverse, previously unexplored β-lactones. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead β-lactone inhibitors/probes for several serine hydrolases, including disease-associated enzymes and enzymes of uncharacterized function. The structural diversity afforded by the α-methylene-β-lactone scaffold thus expands the landscape of serine hydrolases that can be targeted by small-molecule inhibitors and should further the functional characterization of enzymes from this class through the optimization of target-selective probes. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Bioorganic & Medicinal Chemistry Letters 01/2015; 25(2):317-21. DOI:10.1016/j.bmcl.2014.11.038 · 2.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lysophosphatidylserines (lyso-PSs) are a class of signaling lipids that regulate immunological and neurological processes. The metabolism of lyso-PSs remains poorly understood in vivo. Recently, we determined that ABHD12 is a major brain lyso-PS lipase, implicating lyso-PSs in the neurological disease polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC), which is caused by null mutations in the ABHD12 gene. Here, we couple activity-based profiling with pharmacological and genetic methods to annotate the poorly characterized enzyme ABHD16A as a phosphatidylserine (PS) lipase that generates lyso-PS in mammalian systems. We describe a small-molecule inhibitor of ABHD16A that depletes lyso-PSs from cells, including lymphoblasts derived from subjects with PHARC. In mouse macrophages, disruption of ABHD12 and ABHD16A respectively increases and decreases both lyso-PSs and lipopolysaccharide-induced cytokine production. Finally, Abhd16a(-/-) mice have decreased brain lyso-PSs, which runs counter to the elevation in lyso-PS in Abhd12(-/-) mice. Our findings illuminate an ABHD16A-ABHD12 axis that dynamically regulates lyso-PS metabolism in vivo, designating these enzymes as potential targets for treating neuroimmunological disorders.
    Nature Chemical Biology 01/2015; 11(2). DOI:10.1038/nchembio.1721 · 13.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The endocannabinoid ligand 2-arachidonoylglycerol (2-AG) is inactivated primarily by monoacylglycerol lipase (MAGL). We have shown recently that chronic treatments with MAGL inhibitor JZL184 produce antidepressant- and anxiolytic-like effects in a chronic unpredictable stress (CUS) model of depression in mice. However, the underlying mechanisms remain poorly understood. Adult hippocampal neurogenesis has been implicated in animal models of anxiety and depression and behavioral effects of antidepressants. We tested whether CUS and chronic JZL184 treatments affected adult neurogenesis and synaptic plasticity in the dentate gyrus (DG) of mouse hippocampus. We report that CUS induced depressive-like behaviors and decreased the number of bromodeoxyuridine (BrdU)-labeled neural progenitor cells and doublecortin-positive immature neurons in the DG, while chronic JZL184 treatments prevented these behavioral and cellular deficits. We also investigated the effects of CUS and chronic JZL184 on a form long-term potentiation (LTP) in the DG known to be neurogenesis-dependent. CUS impaired LTP induction, whereas chronic JZL184 treatments restored LTP in CUS-exposed mice. These results suggest that enhanced adult neurogenesis and long-term synaptic plasticity in the DG of the hippocampus might contribute to antidepressant- and anxiolytic-like behavioral effects of JZL184. © 2014 Wiley Periodicals, Inc.
    Hippocampus 01/2015; 25(1). DOI:10.1002/hipo.22344 · 4.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inhibition of endocannabinoid catabolic enzymes fatty acid amide hydrolase (FAAH) and/or monoacylglycerol lipase (MAGL) reduces somatic morphine withdrawal signs, but its effects on aversive aspects of withdrawal are unknown. The present study investigated whether Δ(9)-tetrahydrocannabinol (THC), the MAGL inhibitor JZL184, the FAAH inhibitor PF-3845, or the dual FAAH/MAGL inhibitor SA-57 would reduce acquisition of morphine withdrawal-induced conditioned place avoidance (CPA) and jumping. Mice were implanted with placebo or 75mg morphine pellets, 48h later injected with naloxone or saline and placed in the conditioning apparatus, and assessed for CPA at 72h. Subjects were also observed for jumping behavior following naloxone challenge. Naloxone (0.056mg/kg) produced robust CPA in morphine-pelleted, but not placebo-pelleted, mice. Morphine pretreatment prevented the occurrence of withdrawal CPA and withdrawal jumping, while clonidine (an α2 adrenergic receptor agonist) only blocked withdrawal CPA. THC, JZL184, and SA-57 significantly reduced the percentage of mice that jumped during the conditioning session, but did not affect acquisition of withdrawal CPA. PF-3845 did not reduce morphine withdrawal CPA or jumping. Finally, neither THC nor the endocannabinoid catabolic enzyme inhibitors in non-dependent mice elicited a conditioned place preference or aversion. These findings suggest that inhibiting endocannabinoid catabolic enzymes reduces somatic morphine withdrawal signs, but not aversive aspects as inferred in the CPA paradigm. The observation that non-dependent mice administered inhibitors of endocannabinoid degradation did not display place preferences is consistent with the idea that that endocannabinoid catabolic enzymes might be targeted therapeutically, with reduced risk of abuse. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Drug and Alcohol Dependence 01/2015; 146:7-16. DOI:10.1016/j.drugalcdep.2014.11.015 · 3.28 Impact Factor
  • Benjamin F Cravatt, Thomas Kodadek
    Current Opinion in Chemical Biology 12/2014; 24. DOI:10.1016/j.cbpa.2014.12.023 · 7.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mycobacterium tuberculosis (Mtb) maintains its intrabacterial pH (pHIB) near neutrality in the acidic environment of phagosomes within activated macrophages. A previously reported genetic screen revealed that Mtb loses this ability when the mycobacterial acid resistance protease (marP) gene is disrupted. In the present study, a high throughput screen (HTS) of compounds against the protease domain of MarP identified benzoxazinones as inhibitors of MarP. A potent benzoxazinone, BO43 (6-chloro-2-(2'-methylphenyl)-4H-1,3-benzoxazin-4-one), acylated MarP and lowered Mtb's pHIB and survival during incubation at pH 4.5. BO43 had similar effects on MarP-deficient Mtb, suggesting the existence of additional target(s). Reaction of an alkynyl-benzoxazinone, BO43T, with Mycobacterium bovis variant bacille Calmette-Guérin (BCG) followed by click chemistry with azido-biotin identified both the MarP homologue and the high temperature requirement A1 (HtrA1) homologue, an essential protein. Thus, the chemical probe identified through a target-based screen not only reacted with its intended target in the intact cells but also implicated an additional enzyme that had eluded a genetic screen biased against essential genes.
    ACS Chemical Biology 12/2014; 10(2). DOI:10.1021/cb500746z · 5.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity develops when energy intake chronically exceeds energy expenditure. Because brown adipose tissue (BAT) dissipates energy in the form of heat, increasing energy expenditure by augmenting BAT-mediated thermogenesis may represent an approach to counter obesity and its complications. The ability of BAT to dissipate energy is dependent on expression of mitochondrial uncoupling protein 1 (UCP1). To facilitate the identification of pharmacological modulators of BAT UCP1 levels, which may have potential as antiobesity medications, we developed a transgenic model in which luciferase activity faithfully mimics endogenous UCP1 expression and its response to physiologic stimuli. Phenotypic screening of a library using cells derived from this model yielded a small molecule that increases UCP1 expression in brown fat cells and mice. Upon adrenergic stimulation, compound-treated mice showed increased energy expenditure. These tools offer an opportunity to identify pharmacologic modulators of UCP1 expression and uncover regulatory pathways that impact BAT-mediated thermogenesis. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 11/2014; 9(5). DOI:10.1016/j.celrep.2014.10.066 · 7.21 Impact Factor
  • Benjamin F Cravatt
    ACS Chemical Neuroscience 11/2014; 5(11):1083. DOI:10.1021/cn500263c · 4.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle (intracranial self-stimulation, ICSS), which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), while peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide; AEA) and 2-AG. The CB1 receptor antagonist rimonabant, but not the CB2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS. Thus, THC, MAGL inhibition, and dual FAAH-MAGL inhibition not only reduce ICSS, but also decrease other reinforced and non-reinforced behaviors.
    Journal of Pharmacology and Experimental Therapeutics 11/2014; DOI:10.1124/jpet.114.218677 · 3.86 Impact Factor

Publication Stats

27k Citations
3,534.84 Total Impact Points


  • 1994–2015
    • The Scripps Research Institute
      • • Department of Chemical Physiology
      • • Skaggs Institute for Chemical Biology
      • • Department of Cell and Molecular Biology
      • • Department of Chemistry
      لا هویا, California, United States
  • 2013
    • Liverpool School of Tropical Medicine
      Liverpool, England, United Kingdom
    • Abide Therapeutics
      San Diego, California, United States
  • 2010
    • University of Washington Seattle
      Seattle, Washington, United States
  • 2007–2010
    • Pfizer Inc.
      • Pfizer Global Research & Development
      New York City, NY, United States
    • Stanford University
      • Department of Microbiology and Immunology
      Palo Alto, California, United States
  • 2009
    • Indiana University Bloomington
      • Linda and Jack Gill Center for Biomolecular Science
      Bloomington, Indiana, United States
  • 2008
    • University of San Diego
      San Diego, California, United States
  • 2007–2008
    • University of Rome Tor Vergata
      • Dipartimento di Biologia
      Roma, Latium, Italy
  • 2006–2007
    • Vanderbilt University
      • • Department of Biochemistry
      • • Department of Pediatrics
      Нашвилл, Michigan, United States
    • Harvard Medical School
      • Department of Neurobiology
      Boston, Massachusetts, United States
    • University of California, Berkeley
      • Department of Environmental Science, Policy, and Management
      Berkeley, MO, United States
  • 2002–2006
    • Virginia Commonwealth University
      • Department of Pharmacology and Toxicology
      Richmond, VA, United States
  • 2004
    • Complutense University of Madrid
      Madrid, Madrid, Spain