Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation

被引：95

作者：

Hermanson, Daniel J. ^{[1
,2
,3
,4
]}

Hartley, Nolan D. ^{[5
]}

Gamble-George, Joyonna ^{[5
]}

Brown, Naoko ^{[6
]}

Shonesy, Brian C. ^{[7
]}

Kingsley, Phillip J. ^{[1
,2
,3
,4
]}

Colbran, Roger J. ^{[7
]}

Reese, Jeffrey ^{[6
]}

Marnett, Lawrence J. ^{[1
,2
,3
,4
]}

Patel, Sachin ^{[5
,7
]}

机构：

[1] Vanderbilt Univ, Sch Med, AB Hancock Jr Mem Lab Canc Res,Ctr Mol Toxicol, Vanderbilt Inst Chem Biol,Dept Biochem, Nashville, TN 37212 USA

[2] Vanderbilt Univ, Sch Med, AB Hancock Jr Mem Lab Canc Res,Ctr Mol Toxicol, Vanderbilt Inst Chem Biol,Dept Chem, Nashville, TN 37212 USA

[3] Vanderbilt Univ, Sch Med, AB Hancock Jr Mem Lab Canc Res,Ctr Mol Toxicol, Vanderbilt Inst Chem Biol,Dept Pharmacol, Nashville, TN 37212 USA

[4] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37212 USA

[5] Vanderbilt Univ, Sch Med, Dept Psychiat, Nashville, TN 37212 USA

[6] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA

[7] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA

来源：

NATURE NEUROSCIENCE | 2013年 / 16卷 / 09期

基金：

美国国家卫生研究院;

关键词：

AMIDE HYDROLASE INHIBITION; REPEATED HOMOTYPIC STRESS; MOLECULAR CHARACTERIZATION; MONOACYLGLYCEROL LIPASE; CATABOLIC ENZYMES; ARACHIDONIC-ACID; MOUSE-BRAIN; SYSTEM; 2-ARACHIDONOYLGLYCEROL; CYCLOOXYGENASE-2;

D O I：

10.1038/nn.3480

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：1291 / U176

页数：10

共 56 条

[1] Enzymatic pathways that regulate endocannabinoid signaling in the nervous system [J].