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Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum

Nature Neuroscience volume 11, pages 152–159 (2008)Cite this article

Abstract

Of the endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG) have received the most study. A functional interaction between these molecules has never been described. Using mouse brain slices, we found that stimulation of metabotropic glutamate 5 receptors by 3,5-dihydroxyphenylglycine (DHPG) depressed inhibitory transmission in the striatum through selective involvement of 2-AG metabolism and stimulation of presynaptic CB1 receptors. Elevation of AEA concentrations by pharmacological or genetic inhibition of AEA degradation reduced the levels, metabolism and physiological effects of 2-AG. Exogenous AEA and the stable AEA analog methanandamide inhibited basal and DHPG-stimulated 2-AG production, confirming that AEA is responsible for the downregulation of the other eCB. AEA is an endovanilloid substance, and the stimulation of transient receptor potential vanilloid 1 (TRPV1) channels mimicked the effects of endogenous AEA on 2-AG metabolism through a previously unknown glutathione-dependent pathway. Consistently, the interaction between AEA and 2-AG was lost after pharmacological and genetic inactivation of TRPV1 channels.

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Figure 1: Effects of mGlu receptor stimulation on glutamate and GABA transmission recorded from striatal spiny neurons.
Figure 2: eCB system after DHPG in striatal slices.
Figure 3: Interaction of AEA metabolism with 2-AG metabolism and 2-AG's physiological effects.
Figure 4: GABA transmission, mGlu receptor modulation and endocannabinoid metabolism in striatal slices of FAAH knockout and wild-type mice.
Figure 5: Role of Met-AEA and vanilloid receptors in striatal DHPG effects.
Figure 6: GABA transmission, mGlu receptor modulation and endocannabinoid metabolism in striatal slices of TRPV1 knockout mice.
Figure 7: Glutathione levels control 2-AG levels and its physiological effects.

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Acknowledgements

The authors are grateful to P. Spagnuolo for her valuable help with the biochemical assays. This investigation was supported by Italian National Ministero dell'Università e della Ricerca to M.M. and to D.C. (FIRB 2006), by Italian National Ministero della Salute to A.F.A. (grant 2005) and to D.C. (grants 2005 and 2006), by Fondazione TERCAS (Research Programs 2004 and 2005) to M.M., and by Agenzia Spaziale Italiana (Disturbi del Controllo Motorio e Cardiorespiratorio and From Molecules to Man projects 2006) to A.F.-A., G.B. and M.M.

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Authors and Affiliations

  1. Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, Piazza Aldo Moro 45, Teramo, 64100, Italy

    Mauro Maccarrone & Valeria Gasperi

  2. Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Via del Fosso di Fiorano 64, Rome, 00143, Italy

    Mauro Maccarrone, Silvia Rossi, Valentina De Chiara, Filomena Fezza, Alessandra Musella, Chiara Prosperetti, Giorgio Bernardi & Diego Centonze

  3. Dipartimento di Neuroscienze, Clinica Neurologica, Università Tor Vergata, Via Montpellier 1, Rome, 00133, Italy

    Silvia Rossi, Valentina De Chiara, Alessandra Musella, Chiara Prosperetti, Giorgio Bernardi & Diego Centonze

  4. Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Università Tor Vergata, Via Montpellier 1, Rome, 00133, Italy

    Monica Bari, Filomena Fezza & Alessandro Finazzi-Agrò

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

    Benjamin F Cravatt

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Contributions

M.M. planned the biochemical experiments, coordinated the study and revised the draft manuscript. S.R. carried out the electrophysiological recordings, analyzed the data and prepared the figures. M.B., F.F. and V.G. performed the biochemical experiments and analyzed the data. V.D.C., C.P. and A.M. carried out electrophysiological recordings, G.B. and A.F.-A. participated in the study design and revised the draft manuscript, B.F.C. participated in the study design and provided the FAAH knockout mice, and D.C. planned the electrophysiological experiments, coordinated the study and drafted the manuscript. All authors contributed to the discussion and interpretation of the results.

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Correspondence to Mauro Maccarrone or Diego Centonze.

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Maccarrone, M., Rossi, S., Bari, M. et al. Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum. Nat Neurosci 11, 152–159 (2008). https://doi.org/10.1038/nn2042

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