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

Mauro Maccarrone, Silvia Rossi, Monica Bari, Valentina De Chiara, Filomena Fezza, Alessandra Musella, Valeria Gasperi, Chiara Prosperetti, Giorgio Bernardi, Alessandro Finazzi-Agrò, Benjamin F. Cravatt, Diego Centonze

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)152-159
Number of pages8
JournalNature Neuroscience
Issue number2
Publication statusPublished - Feb 2008

ASJC Scopus subject areas

  • Neuroscience(all)


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