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Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects

Nature Chemical Biology volume 5, pages 37–44 (2009)Cite this article

Abstract

2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate the cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that for anandamide is mediated by fatty acid amide hydrolase (FAAH), and for 2-AG is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, which suggests a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL called JZL184 that, upon administration to mice, raises brain 2-AG by eight-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.

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Figure 1: Structures and competitive ABPP profiles of MAGL inhibitors.
Figure 2: In vitro characterization of JZL184.
Figure 3: In vivo characterization of JZL184.
Figure 4: JZL184 raises interstitial levels of 2-AG following neuronal depolarization.
Figure 5: Time course analysis of inhibitory activity of JZL184 in vivo.
Figure 6: Behavioral effects of JZL184.

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Acknowledgements

We thank the Cravatt lab for helpful discussion and critical reading of the manuscript. This work was supported by the US National Institutes of Health (DA017259, DA025285, DA007027, DA005274 AA014619, DA024194 and AA06420), the Helen L. Dorris Institute Child and Adolescent Neuro-Psychiatric Disorder Institute and the Skaggs Institute for Chemical Biology.

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Authors and Affiliations

  1. The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Jonathan Z Long, Weiwei Li & Benjamin F Cravatt

  2. The Committee on the Neurobiology of Addiction, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Franciso J Pavón, Antonia M Serrano & Loren H Parsons

  3. Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, 23298, Virginia, USA

    Lamont Booker, James J Burston, Steven G Kinsey, Joel E Schlosburg, Dana E Selley & Aron H Lichtman

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Contributions

J.Z.L., L.H.P., A.H.L. and B.F.C. designed the experiments. J.Z.L. and W.L. synthesized and characterized the inhibitors. F.J.P., A.M.S. and L.H.P. measured extracellular endocannabinoid levels. L.B., J.J.B., S.G.K., J.E.S., D.E.S. and A.H.L. performed behavioral studies. J.Z.L. and B.F.C. wrote the manuscript.

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Correspondence to Benjamin F Cravatt.

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Supplementary Figures 1–8, Supplementary Table 1, Supplementary Methods (PDF 1814 kb)

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Long, J., Li, W., Booker, L. et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol 5, 37–44 (2009). https://doi.org/10.1038/nchembio.129

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