The CB1 Neutral Antagonist AM4113 Retains the Therapeutic Efficacy of the Inverse Agonist Rimonabant for Nicotine Dependence and Weight Loss with Better Psychiatric Tolerability
The CB1 Neutral Antagonist AM4113 Retains the Therapeutic Efficacy of the Inverse Agonist Rimonabant for Nicotine Dependence and Weight Loss with Better Psychiatric Tolerability
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DOI：
10.1093/ijnp/pyw068
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发表时间：
2016-12-01
影响因子：
4.8
通讯作者：
Le Foll, Bernard
中科院分区：
文献类型：
--
作者：
Gueye, Aliou B.;Pryslawsky, Yaroslaw;Le Foll, Bernard
背景资料：多项研究表明，内源性大麻素系统在调节各种滥用物质的强化作用方面发挥着关键作用。利莫那班是一种CB 1反向激动剂，被发现对戒烟有效，与焦虑和抑郁的风险增加有关。在这里，我们评估了CB 1中性拮抗剂AM4113对尼古丁的滥用相关效应及其对大鼠焦虑和抑郁样行为的影响。方法：大鼠接受训练，以固定比例5或渐进比例强化计划下自我管理尼古丁。对照组接受自我喂食训练。评价了AM4113预处理对尼古丁摄入、尼古丁动机以及线索、尼古丁引发和育亨宾诱导的尼古丁寻求恢复的急性/慢性效应。在用尼古丁处理的单独一组动物中评价了AM4113对中脑多巴胺神经元的基础放电和爆发活性的影响。在慢性（21天）预处理（0、1、3和10 mg/kg，1/d）后24 h评估AM4113和利莫那班的焦虑/抑郁样效应。结果：AM4113显著减弱尼古丁摄入、尼古丁动机以及线索、引发和应激诱导的尼古丁寻求行为的恢复。这些影响伴随着减少的放电和突发率在腹侧被盖区多巴胺神经元响应尼古丁。另一方面，AM 4113预处理对食物的操作性反应没有影响。重要的是，AM4113并没有对焦虑的影响，并表现出抗抑郁样effects.Conclusion：我们的研究结果表明，AM4113可能是一个很有前途的治疗选择，用于预防尼古丁寻求复发，同时缺乏焦虑/抑郁样副作用。
Background: Multiple studies suggest a pivotal role of the endocannabinoid system in regulating the reinforcing effects of various substances of abuse. Rimonabant, a CB 1 inverse agonist found to be effective for smoking cessation, was associated with an increased risk of anxiety and depression. Here we evaluated the effects of the CB 1 neutral antagonist AM4113 on the abuse-related effects of nicotine and its effects on anxiety and depressive-like behavior in rats.Methods: Rats were trained to self-administer nicotine under a fixed-ratio 5 or progressive-ratio schedules of reinforcement. A control group was trained to self-administer food. The acute/chronic effects of AM4113 pretreatment were evaluated on nicotine taking, motivation for nicotine, and cue-, nicotine priming-and yohimbine-induced reinstatement of nicotine-seeking. The effects of AM4113 in the basal firing and bursting activity of midbrain dopamine neurons were evaluated in a separate group of animals treated with nicotine. Anxiety/depression-like effects of AM4113 and rimonabant were evaluated 24 h after chronic (21 days) pretreatment (0, 1, 3, and 10 mg/kg, 1/d).Results: AM4113 significantly attenuated nicotine taking, motivation for nicotine, as well as cue-, priming-and stress-induced reinstatement of nicotine-seeking behavior. These effects were accompanied by a decrease of the firing and burst rates in the ventral tegmental area dopamine neurons in response to nicotine. On the other hand, AM4113 pretreatment did not have effects on operant responding for food. Importantly, AM4113 did not have effects on anxiety and showed antidepressant-like effects.Conclusion: Our results indicate that AM4113 could be a promising therapeutic option for the prevention of relapse to nicotine-seeking while lacking anxiety/depression-like side effects.