Editors' ChoiceNeuroscience

Endocannabinoid Interactions

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Science Signaling  05 Feb 2008:
Vol. 1, Issue 5, pp. ec45
DOI: 10.1126/stke.15ec45

Noting that stimulation of metabotropic glutamate (mGlu) receptors attenuates release of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in various brain regions by means of retrograde endocannabinoid signaling through presynaptic CB1 receptors (see Di Marzo and Cristino), Maccarrone et al. investigated endocannabinoid signaling in the striatum. A combination of pharmacological and electrophysiological analysis of striatal slices revealed that activation of mGlu5 receptors with 3,5-dihydroxyphenylglycine (DHPG) led to the CB1-dependent inhibition of GABA release. There are two principal endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and DHPG increased 2-AG concentration, but not that of anandamide, by stimulating activity of the 2-AG synthetic enzyme diacylglycerol lipase (DAGL) and inhibiting activity of the 2-AG degrading enzyme monoacylglycerol lipase (MAGL). Although functional interactions between anandamide and 2-AG had not previously been shown, pharmacological inhibition of fatty acid amide hydrolase (FAAH, the enzyme that degrades anandamide) blocked the DHPG-mediated increase in 2-AG and prevented its effects on GABAergic transmission, as did FAAH knockout. The stable anandamide derivative methanandamide also blocked DHPG-mediated increase in 2-AG and decreased basal 2-AG. Anandamide activates transient receptor potential vanilloid 1 (TRPV1) channels, and the TRPV1 agonist capsaicin inhibited the effects of DHPG on 2-AG concentration and GABAergic transmission as well, whereas pharmacological inhibition of FAAH and capsaicin failed to block the effects of DHPG on 2-AG and GABAergic transmission in mice lacking TRPV1. Manipulations that increased anandamide concentration were associated with decreased DAGL activity, and capsaicin blocked a DHPG-dependent increase in striatal glutathione (which stimulates DAGL). Thus, anandamide can inhibit the production and effects of striatal 2-AG through activation of TRPV1, effects that seem to involve a glutathione-dependent pathway.

M. Maccarrone, S. Rossi, M. Bari, V. De Chiara, F. Fezza, A. Musella, V. Gasperi, C. Prosperetti, G. Bernardi, A. Finazzi-Agrò, B. F Cravatt, D. Centonze, Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum. Nat. Neurosci. 11, 152-159 (2008). [PubMed]

V. Di Marzo, L. Cristino, Why endocannabinoids are not all alike. Nat. Neurosci. 11, 124-126 (2008). [PubMed]

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