title: Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation.
abstract: Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro. However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Using medicinal chemistry and in vivo analytical and behavioral pharmacological approaches, we found that COX-2 is important for the regulation of eCB levels in vivo. We used a pharmacological strategy involving substrate-selective inhibition of COX-2 to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2 reduced anxiety-like behaviors in mice via increased eCB signaling. Our data suggest a key role for COX-2 in the regulation of eCB signaling and indicate that substrate-selective pharmacology represents a viable approach for eCB augmentation with broad therapeutic potential.
authors.affiliation: A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hermanson
authors.forename: Nolan D
authors.initials: ND
authors.lastname: Hartley
authors.forename: Joyonna
authors.initials: J
authors.lastname: Gamble-George
authors.forename: Naoko
authors.initials: N
authors.lastname: Brown
authors.forename: Brian C
authors.initials: BC
authors.lastname: Shonesy
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Kingsley
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Reese
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.forename: Sachin
authors.initials: S
authors.lastname: Patel
mesh_terms: D000221:Adaptation, Ocular / Q000187:drug effects / Q000235:genetics; D000581:Amidohydrolases / Q000172:deficiency; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D048588:Benzoxazines / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics; D002121:Calcium Channel Blockers / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D063388:Endocannabinoids; D007211:Indoles; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C578453:CNR1 protein, mouse; C584077:LM-4131; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C077623:Ptgs2 protein, mouse
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