Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Canada.
Addict Biol. 2012 Jan;17(1):47-61. doi: 10.1111/j.1369-1600.2011.00314.x. Epub 2011 Apr 26.
The cannabinoid system appears to play a critical facilitative role in mediating the reinforcing effects of nicotine and relapse to nicotine-seeking behaviour in abstinent subjects based on the actions of cannabinoid (CB) receptor antagonists. However, the effects of CB receptor stimulation on nicotine self-administration and reinstatement have not been systematically studied. Here, we studied the effects of WIN 55,212-2, a CB1/2 agonist, on intravenous nicotine self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement in rats. The effects of WIN 55,212-2 on responding for food under similar schedules were also studied. In addition, the effects of WIN 55,212-2 on nicotine- and cue-induced reinstatement of nicotine seeking were also studied, as well as the effects of WIN 55,212-2 on nicotine discrimination. WIN 55,212-2 decreased nicotine self-administration under the FR schedule. However, co-administration of WIN 55,212-2 with nicotine decreased responding for food, which suggests that this effect was non-selective. In contrast, WIN 55,212-2 increased both nicotine self-administration and responding for food under the PR schedule, produced dose-dependent reinstatement of nicotine seeking, and enhanced the reinstatement effects of nicotine-associated cues. Some of these effects were reversed by the CB1 antagonist rimonabant, but not by the CB2 antagonist AM630. In the drug discrimination tests between saline and 0.4 mg/kg nicotine, WIN 55,212-2 produced no nicotine-like discriminative effects but significantly potentiated discriminative stimulus effects of nicotine at the low dose through a CB1-receptor-dependent mechanism. These findings indicate that cannabinoid CB1-receptor stimulation increases the reinforcing effects of nicotine and precipitates relapse to nicotine-seeking behaviour in abstinent subjects. Thus, modulating CB1-receptor signalling might have therapeutic value for treating nicotine dependence.
大麻素系统似乎在介导尼古丁的强化作用以及在戒烟者中引发尼古丁觅药行为的复吸方面发挥着关键的促进作用，这是基于大麻素（CB）受体拮抗剂的作用。然而，CB 受体刺激对尼古丁自我给药和复吸的影响尚未得到系统研究。在这里，我们研究了 WIN 55,212-2（一种 CB1/2 激动剂）对大鼠在固定比率（FR）和渐进比率（PR）强化方案下静脉注射尼古丁自我给药的影响。还研究了 WIN 55,212-2 对类似方案下食物反应的影响。此外，还研究了 WIN 55,212-2 对尼古丁和线索诱导的尼古丁觅药复吸的影响，以及 WIN 55,212-2 对尼古丁辨别力的影响。WIN 55,212-2 降低了 FR 方案下的尼古丁自我给药。然而，WIN 55,212-2 与尼古丁共同给药会减少食物反应，这表明这种作用是非选择性的。相比之下，WIN 55,212-2 在 PR 方案下增加了尼古丁自我给药和食物反应，产生了剂量依赖性的尼古丁觅药复吸，并增强了尼古丁相关线索的复吸效应。这些作用中的一些被 CB1 拮抗剂利莫那班逆转，但不能被 CB2 拮抗剂 AM630 逆转。在盐水和 0.4mg/kg 尼古丁之间的药物辨别测试中，WIN 55,212-2 没有产生类似尼古丁的辨别作用，但通过 CB1 受体依赖的机制，显著增强了尼古丁低剂量的辨别刺激作用。这些发现表明，大麻素 CB1 受体刺激增加了尼古丁的强化作用，并在戒烟者中引发了对尼古丁觅药行为的复吸。因此，调节 CB1 受体信号可能对治疗尼古丁依赖具有治疗价值。
