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Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus

Nature Neuroscience volume 8, pages 1139–1141 (2005)Cite this article

A Corrigendum to this article was published on 01 January 2007

This article has been updated

Abstract

The functions of 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid found in the brain, remain largely unknown. Here we show that two previously unknown inhibitors of monoacylglycerol lipase, a presynaptic enzyme that hydrolyzes 2-AG, increase 2-AG levels and enhance retrograde signaling from pyramidal neurons to GABAergic terminals in the hippocampus. These results establish a role for 2-AG in synaptic plasticity and point to monoacylglycerol lipase as a possible drug target.

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Figure 1: URB754 is a potent MGL inhibitor.
Figure 2: Inhibition of MGL, but not FAAH, activity prolongs DSI in CA1 pyramidal cells.

Change history

  • 12 December 2006

    Our paper identified 6-methyl-2-p-tolylaminobenzo[d]oxazin-4-one (URB754; Specs) as a monoacylglycerol lipase (MGL) inhibitor that enhances hippocampal depolarization-induced suppression of inhibition (DSI). However, in subsequent tests of non-commercial URB754, we failed to replicate these results, suggesting that a bioactive impurity was present in the commercial material. We have identified this impurity as bis(methylthio)mercurane (Supplementary Results online). Because this compound interacts with multiple targets, we tested another MGL inhibitor, methylarachidonylfluorophosphonate (MAFP), which prolonged DSI (Fig. 1), confirming that monoacylglycerol lipase contributes to the termination of DSI, as others have reported1. Another generation of endocannabinoid metabolism inhibitors is needed to test this hypothesis further.

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Acknowledgements

We thank N. Hájos for valuable comments and J. Kim for help with cultures. This research was supported by grants from the US National Institute on Drug Abuse and the University of California Discovery Program (D.P.); from Ministero Istruzione Università e Ricerca and University of Urbino 'Carlo Bo' and University of Parma (G.T. and M.M.); and from the Howard Hughes Medical Institute, US National Institutes of Health, European Union Framework Programme 6 and Országos Tudományos Kutatási Alapprogramok (T.F.F).

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Affiliations

  1. Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, 8. Szigony u. 43., Budapest, H-1083, Hungary

    Judit K Makara, Szilárd I Szabó & Tamás F Freund

  2. Pharmaceutical Department, University of Parma, Parco Area delle Scienze, 27/A, Parma, I-43100, Italy

    Marco Mor & Silvia Rivara

  3. Department of Pharmacology, University of California Irvine, Irvine, 92697-4625, California, USA

    Darren Fegley, Satish Kathuria, Giuseppe Astarita & Daniele Piomelli

  4. Institute of Medicinal Chemistry, University of Urbino 'Carlo Bo', Piazza del Rinascimento, 6, Urbino, I-61029, Italy

    Andrea Duranti, Andrea Tontini & Giorgio Tarzia

  5. Center for Drug Discovery, University of California Irvine, Irvine, 92697-4625, California, USA

    Darren Fegley, Satish Kathuria, Giuseppe Astarita & Daniele Piomelli

Authors
  1. Judit K Makara
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  2. Marco Mor
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  3. Darren Fegley
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  4. Szilárd I Szabó
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  11. Tamás F Freund
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  12. Daniele Piomelli
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Corresponding authors

Correspondence to Tamás F Freund or Daniele Piomelli.

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Competing interests

The authors declare competing financial interests: a patent was filed on behalf of D.P., A.D., A.T., M.M. and G.T. by the University of California, Irvine; the University of Urbino and the University of Parma.

Supplementary information

Supplementary Fig. 1

The effect of URB602 on DSI is mediated by CB1 receptors. (PDF 184 kb)

Supplementary Fig. 2

URB602 does not affect depolarization-evoked Ca2+ transients in hippocampal CA1 pyramidal neurons. (PDF 635 kb)

Supplementary Fig. 3

URB754 and URB602 do not inhibit FAAH activity in rat forebrain slice cultures. (PDF 562 kb)

Supplementary Fig. 4

Effects of a high concentration of URB754 (3 μM) on hippocampal DSI. (PDF 1137 kb)

Supplementary Table 1

Kinetic analysis of the effects of URB754 on the activity of recombinant rat brain MGL expressed in HeLa cells. (PDF 38 kb)

Supplementary Methods (PDF 128 kb)

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Makara, J., Mor, M., Fegley, D. et al. Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nat Neurosci 8, 1139–1141 (2005). https://doi.org/10.1038/nn1521

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