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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidohydrolases / deficiency
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Animals
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Arachidonic Acids / pharmacology*
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Arachidonic Acids / physiology*
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Cannabinoid Receptor Modulators / pharmacology*
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Corpus Striatum / cytology
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Corpus Striatum / drug effects*
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Down-Regulation / drug effects
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Drug Interactions
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Endocannabinoids
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Glutathione / metabolism
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Glycerides / physiology*
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In Vitro Techniques
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Methoxyhydroxyphenylglycol / analogs & derivatives
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Methoxyhydroxyphenylglycol / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neurons / drug effects
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Patch-Clamp Techniques / methods
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Polyunsaturated Alkamides / pharmacology*
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Protein Binding / drug effects
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Protein Binding / genetics
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Receptor, Cannabinoid, CB1 / metabolism
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Synaptic Transmission / drug effects
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Synaptic Transmission / genetics
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TRPV Cation Channels / deficiency
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Time Factors
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gamma-Aminobutyric Acid / pharmacology
Substances
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Arachidonic Acids
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Cannabinoid Receptor Modulators
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Endocannabinoids
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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Glycerides
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Polyunsaturated Alkamides
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Receptor, Cannabinoid, CB1
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TRPV Cation Channels
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TRPV1 protein, mouse
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Methoxyhydroxyphenylglycol
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gamma-Aminobutyric Acid
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glyceryl 2-arachidonate
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Amidohydrolases
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fatty-acid amide hydrolase
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Glutathione
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3,4-dihydroxyphenylglycol
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anandamide