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.

1. Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, Piazza Aldo Moro 45, 64100 Teramo, Italy.
2. Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143 Rome, Italy.
3. Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
4. Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
5. Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

Correspondence to: Mauro Maccarrone^1,2 e-mail: mmaccarrone@unite.it

Correspondence to: Diego Centonze^2,3 e-mail: centonze@uniroma2.it

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