Cippitelli Andrea, Bilbao Ainhoa, Gorriti Miguel Angel, Navarro Miguel, Massi Maurizio, Piomelli Daniele, Ciccocioppo Roberto, Rodríguez de Fonseca Fernando
Fundación IMABIS (The European TARGALC Consortium), Hospital Carlos Haya, Avenida Carlos Haya s/n, 7 Planta, Pabellón A, 29010 Málaga, Spain.
Eur J Neurosci. 2007 Jul;26(2):476-86. doi: 10.1111/j.1460-9568.2007.05665.x.
The endocannabinoid system mediates in the pharmacological actions of ethanol and genetic studies link endocannabinoid signaling to alcoholism. Drugs activating cannabinoid CB1 receptors have been found to promote alcohol consumption but their effects on self-administration of alcohol are less clear because of the interference with motor performance. To avoid this problem, a novel pharmacological approach to the study of the contribution of the cannabinoid system in alcoholism may be to use drugs that locally amplify the effects of alcohol on endogenous cannabinoids. In the present study we addressed this model by studying the effects of the anandamide transport inhibitor N-(4-hydroxyphenyl) arachidonoyl-ethanolamide (AM404) on both ethanol self-administration and reinstatement of alcohol-seeking behavior in rats. The results show that AM404 significantly reduced ethanol self-administration in a dose-dependent manner but failed to modify reinstatement for lever pressing induced by the stimulus associated with alcohol. This effect was not due to a motor depressant effect and was not related to a decrease in general motivational state, as it was not effective in other reward paradigms such as lever pressing for a saccharin solution. The mechanism of action of AM404 does not involve cannabinoid CB1 receptors as the CB1-selective antagonist SR141716A did not block the reduction of ethanol self-administration induced by the anandamide uptake blocker. Moreover, 3-(1,1-dimethylheptyl)-(-)-11-hydroxy-delta 8-tetrahydrocannabinol (HU-210), a classical cannabinoid receptor agonist, did not affect ethanol self-administration. The effects of AM404 are not mediated by either vanilloid VR1 receptors or cannabinoid CB2 receptors because it is not antagonized by either the VR1 receptor antagonist capsazepine or the CB2 antagonist AM630. These results indicate that AM404 may be considered as an innovative approach to reduce alcohol consumption.
内源性大麻素系统介导乙醇的药理作用，并且遗传学研究将内源性大麻素信号传导与酒精中毒联系起来。已发现激活大麻素CB1受体的药物会促进酒精摄入，但由于对运动表现的干扰，它们对酒精自我给药的影响尚不清楚。为避免此问题，一种研究大麻素系统在酒精中毒中作用的新型药理学方法可能是使用能局部增强酒精对内源性大麻素作用的药物。在本研究中，我们通过研究花生四烯酸乙醇胺转运抑制剂N-(4-羟基苯基)花生四烯酸乙醇胺(AM404)对大鼠乙醇自我给药和酒精寻求行为恢复的影响来探讨该模型。结果表明，AM404以剂量依赖性方式显著降低乙醇自我给药，但未能改变与酒精相关的刺激诱导的杠杆按压行为的恢复。这种作用不是由于运动抑制作用，也与一般动机状态的降低无关，因为它在其他奖励范式如杠杆按压获取糖精溶液中无效。AM404的作用机制不涉及大麻素CB1受体，因为CB1选择性拮抗剂SR141716A不能阻断花生四烯酸乙醇胺摄取阻滞剂诱导的乙醇自我给药的减少。此外，经典大麻素受体激动剂3-(1,1-二甲基庚基)-(-)-11-羟基-δ8-四氢大麻酚(HU-210)不影响乙醇自我给药。AM404的作用不是由香草酸受体VR1或大麻素CB2受体介导的，因为它既不被VR1受体拮抗剂辣椒素也不被CB2拮抗剂AM630拮抗。这些结果表明，AM404可被视为一种减少酒精摄入的创新方法。
