Abstract
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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