Anandamide, an endogenous cannabinoid, has a very low physical dependence potential.
Anandamide, an endogenous cannabinoid, has a very low physical dependence potential.
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发表时间：
1998-11
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通讯作者：
Mario D. Aceto;S. Scates;R. Razdan;Billy R. Martin
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作者：
Mario D. Aceto;S. Scates;R. Razdan;Billy R. Martin
使用N-（哌啶-1-基）-5-（4-氯苯基）-1-（2，4-二氯-苯基）-4-甲基-1H-吡唑-3-甲酰胺。HCl（SR 141716 A），一种大麻素拮抗剂，几个研究者（deFonseca等人，1997; Aceto等人，1995，1996; Tsou等人，1995）表现出对THC [Δ 9-四氢大麻酚]的身体依赖性。这一证明促使我们确定内源性大麻素激动剂anandamide是否也会产生身体依赖。分别从第1天至第4天连续腹腔注射低剂量方案（10、20、40和40）或高剂量方案（25、50、100和100），表示为mg/kg/24小时。输注期间，尤其是高剂量方案，大鼠变得不动并出现眼睑下垂。突然停用大麻素不会引起反弹行为活动。花生四烯酸（一种花生四烯酸的前体和代谢物）（第1天至第4天分别为50、100、200和200 mg/kg/24小时）和2-Me-F-AN [2-甲基花生四烯酸基-（2 '-氟乙基）-酰胺]（一种花生四烯酸的代谢稳定类似物）（分别为5、10、20和20 mg/kg/24小时，持续4天）均无显著影响。值得注意的是，与SR 141716 A对照相比，用花生四烯酸或2-Me-F-AN预处理并用SR 141716 A攻击的组未显示出显著升高的行为评分。另一方面，与溶剂对照组相比，几乎所有接受SR 141716 A的组均显示出这些行为的显著激活，这表明这种大麻素拮抗剂本身就是激活行为。我们的结论是，花生四烯酸酰胺几乎没有任何身体依赖性。SR 141716 A激活行为的发现支持大麻拟似物系统在CNS中发挥抑制作用的假设。
Using N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide. HCl (SR 141716A), a cannabinoid antagonist, several investigators (deFonseca et al., 1997; Aceto et al., 1995, 1996; Tsou et al., 1995) demonstrated physical dependence on THC [Delta9-tetrahydrocannabinol]. This demonstration prompted us to determine whether anandamide, an endogenous cannabinoid agonist, would also produce physical dependence. A low-dose regimen (10, 20, 40 and 40) or a high-dose regimen (25, 50, 100 and 100) expressed as mg/kg/24 hr was infused i.p. on a continuous basis, from days 1 through 4, respectively. During the infusion, especially at the high-dose regimen, the rats became immobile and developed eyelid ptosis. Abrupt discontinuation of anandamide did not elicit rebound behavioral activity. Neither arachidonic acid, a precursor and metabolite of anandamide (50, 100, 200 and 200 mg/kg/24 hr on days 1 through 4, respectively), nor 2-Me-F-AN [2-methylarachidonyl-(2'-fluoroethyl)-amide], a metabolically stable analog of anandamide (5, 10, 20 and 20 mg/kg/24 hr for 4 days, respectively), had remarkable effects. Notably, groups pretreated with anandamide or 2-Me-F-AN and challenged with SR 141716A did not show significantly elevated behavioral scores when compared with SR 141716A controls. On the other hand, nearly all groups receiving SR 141716A showed significant activation of these behaviors compared with vehicle controls, which suggests that this cannabinoid antagonist itself was activating behavior. We concluded that anandamide has little if any capacity for physical dependence. The finding that SR 141716A activated behavior supports the hypothesis that the cannabimimetic system exerts a depressant effect in the CNS.