Forget Benoit, Coen Kathleen M, Le Foll Bernard
Translational Addiction Research Laboratory, Centre for Addiction and Mental Health (CAMH), Toronto, Canada, M5S 2S1.
Psychopharmacology (Berl). 2009 Sep;205(4):613-24. doi: 10.1007/s00213-009-1569-5. Epub 2009 May 30.
The endocannabinoid system has been recently identified as having critical involvement in drug taking and relapse phenomenon for various drugs of abuse and notably nicotine. The endocannabinoid system consists of endocannabinoids (such as anandamide), their target receptors (mostly cannabinoid CB(1) receptors), and the enzymes that degrade those endocannabinoids (fatty-acid-amide-hydrolase (FAAH) for anandamide). It has been recently identified that the utility of rimonabant for smoking cessation may be limited by its psychiatric side effects. Therefore, there is a great need to develop alternative ways of modulating the cannabinoid system that will be better tolerated.
The aim of the study was to explore the effect of inhibiting FAAH enzyme by URB597 on nicotine self-administration under a progressive ratio schedule and reinstatement of nicotine seeking, in comparison with the effect of the CB(1) antagonist rimonabant.
Rimonabant, but not URB597, dose-dependently reduced the break point for nicotine self-administration, an effect that was stable over repeated administrations. Rimonabant and URB597 significantly decreased the reinstatement of nicotine seeking induced either by presentation of nicotine-associated stimuli or by nicotine priming.
These results indicate that the integrity of the CB(1) receptors is necessary for the incentive motivation of the rats for nicotine and that FAAH inhibition may be as effective as CB(1) receptor blockade to prevent reinstatement of nicotine seeking. Since FAAH inhibition present antidepressant and anxiolytic properties in rodents, targeting the FAAH may represent a novel strategy to prevent relapse for tobacco smoking that may be better tolerated than rimonabant.
内源性大麻素系统最近被发现与多种滥用药物尤其是尼古丁的药物成瘾及复吸现象密切相关。内源性大麻素系统由内源性大麻素（如花生四烯乙醇胺）、其靶受体（主要是大麻素CB(1)受体）以及降解这些内源性大麻素的酶（花生四烯酸酰胺水解酶（FAAH）负责降解花生四烯乙醇胺）组成。最近发现，利莫那班用于戒烟的效用可能因其精神方面的副作用而受到限制。因此，迫切需要开发出耐受性更好的调节大麻素系统的替代方法。
本研究旨在探讨与CB(1)拮抗剂利莫那班相比，URB597抑制FAAH酶对渐进比率程序下尼古丁自我给药及尼古丁觅求恢复的影响。
利莫那班而非URB597能剂量依赖性地降低尼古丁自我给药的断点，且该效应在重复给药时稳定。利莫那班和URB597均能显著降低由呈现尼古丁相关刺激或尼古丁激发所诱导的尼古丁觅求恢复。
这些结果表明，CB(1)受体的完整性对于大鼠对尼古丁的激励动机是必要的，并且抑制FAAH在预防尼古丁觅求恢复方面可能与阻断CB(1)受体一样有效。由于抑制FAAH在啮齿动物中具有抗抑郁和抗焦虑特性，靶向FAAH可能代表一种预防吸烟复吸的新策略，其耐受性可能比利莫那班更好。
