Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates.
Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates.
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DOI：
10.1016/j.biopsych.2008.08.008
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发表时间：
2008-12-01
影响因子：
10.6
通讯作者：
Goldberg, Steven R.
中科院分区：
文献类型：
--
作者：
Justinova, Zuzana;Mangieri, Regina A.;Bortolato, Marco;Chefer, Svetlana I.;Mukhin, Alexey G.;Clapper, Jason R.;King, Alvin R.;Redhi, Godfrey H.;Yasar, Sevil;Piomelli, Daniele;Goldberg, Steven R.
众所周知，大脑中的CB1大麻素受体参与了基于奖励的行为的调节，然而，内源性大麻素递质anandamide和2-花生四烯醇甘油（2-AG）对这些行为的贡献尚不清楚。为了解决这个问题，我们评估了URB597（一种选择性阿南达胺失活抑制剂）作为松鼠猴药物寻求和药物服用行为强化物的作用。我们研究了脂肪酸酰胺水解酶（FAAH）抑制剂URB597对猴子的强化作用，训练它们静脉注射Δ9-tetrahydrocannabinol （THC）、阿南达明（anandamide）或可卡因，并使用液相色谱/质谱法定量脑内源性大麻素水平。我们使用体外酶测定法测量脑FAAH活性。URB597 （0.3 mg/kg，静脉注射）阻断FAAH活性，增加整个猴子大脑的anandamide水平。这种效应伴随着2-AG水平的显著代偿性降低。猴子没有自我使用URB597，并且该药物不会促进先前由四氢大麻酚、阿南达胺或可卡因维持的已消失的药物寻求行为的恢复。urban - 597预处理并没有改变四氢大麻酚或可卡因的自我给药，尽管正如预期的那样，它显著增强了阿南达胺的自我给药。在猴子大脑中，FAAH抑制剂URB597增加了anandamide水平，同时引起2-AG水平的代偿性下调。这些影响伴随着显著缺乏增强特性，这将URB597与直接作用的大麻素激动剂（如四氢大麻酚）区分开来。我们的研究结果揭示了内源性大麻素信号系统中意想不到的功能异质性，并表明FAAH抑制剂可能用于治疗而没有滥用或引发药物滥用复发的风险。
CB1 cannabinoid receptors in the brain are known to participate in the regulation of reward-based behaviors, however, the contribution of each of the endocannabinoid transmitters, anandamide and 2-arachidonoylglycerol (2-AG), to these behaviors remains undefined. To address this question, we assessed the effects of URB597, a selective anandamide deactivation inhibitor, as a reinforcer of drug-seeking and drug-taking behavior in squirrel monkeys. We investigated the reinforcing effects of the fatty acid amide hydrolase (FAAH) inhibitor URB597 in monkeys trained to intravenously self-administer Δ9-tetrahydrocannabinol (THC), anandamide or cocaine, and quantified brain endocannabinoid levels using liquid chromatography/mass spectrometry. We measured brain FAAH activity using an ex vivo enzyme assay. URB597 (0.3 mg/kg, intravenous) blocked FAAH activity and increased anandamide levels throughout the monkey brain. This effect was accompanied by a marked compensatory decrease in 2-AG levels. Monkeys did not self-administer URB597 and the drug did not promote reinstatement of extinguished drug-seeking behavior previously maintained by THC, anandamide, or cocaine. Pretreatment with URB597 did not modify self-administration of THC or cocaine even though, as expected, it significantly potentiated anandamide self-administration. In the monkey brain, the FAAH inhibitor URB597 increases anandamide levels while causing a compensatory down-regulation in 2-AG levels. These effects are accompanied by a striking lack of reinforcing properties, which distinguishes URB597 from direct-acting cannabinoid agonists such as THC. Our results reveal an unexpected functional heterogeneity within the endocannabinoid signaling system, and suggest that FAAH inhibitors might be used therapeutically without risk of abuse or triggering of relapse to drug abuse.
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影响因子：
2.7
作者：
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通讯作者：
SCHUSTER, CR
影响因子：
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作者：
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