Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum.
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.
Maccarrone
Mauro
M
Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, Piazza Aldo Moro 45, 64100 Teramo, Italy. mmaccarrone@unite.it
Rossi
Silvia
S
Bari
Monica
M
De Chiara
Valentina
V
Fezza
Filomena
F
Musella
Alessandra
A
Gasperi
Valeria
V
Prosperetti
Chiara
C
Bernardi
Giorgio
G
Finazzi-Agrò
Alessandro
A
Cravatt
Benjamin F
BF
Centonze
Diego
D
D000581:Amidohydrolases / Q000172:deficiency; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology* / Q000502:physiology*; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D005989:Glycerides / Q000502:physiology*; D066298:In Vitro Techniques; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D050916:TRPV Cation Channels / Q000172:deficiency; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005978:Glutathione; D005989:Glycerides; D008734:Methoxyhydroxyphenylglycol; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; D005680:gamma-Aminobutyric Acid; D000099252:Fatty Acid Amide Hydrolases; C493921:TRPV1 protein, mouse; C094503:glyceryl 2-arachidonate; C010117:3,4-dihydroxyphenylglycol; C078814:anandamide