Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers.
Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers.
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DOI：
10.1038/tp.2015.209
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发表时间：
2016-01-19
影响因子：
6.8
通讯作者：
Schmidt HD
中科院分区：
文献类型：
--
作者：
Ashare RL;Kimmey BA;Rupprecht LE;Bowers ME;Hayes MR;Schmidt HD
吸烟仍然是世界范围内可预防死亡的主要原因，目前的戒烟药物疗效有限。因此，明确需要进行转化研究，重点是确定尼古丁成瘾的新药物疗法。我们之前的研究表明，急性给药乙酰胆碱酯酶抑制剂（AChEI）可以减少大鼠对尼古丁的摄入和寻求，并表明AChEI可以重新用于戒烟。在这里，我们通过实验来扩展这些发现，旨在确定反复给药乙酰胆碱抑制剂对大鼠自愿尼古丁摄入以及人类吸烟者吸烟行为的影响。训练大鼠自行静脉注射尼古丁（0.03 mg kg - 1 / 0.59 ml），固定比例为5。一旦大鼠保持稳定的尼古丁摄入，在连续10次的每日尼古丁自我给药之前给药加兰他明或多奈哌齐。反复给药5.0 mg kg - 1加兰他明和3.0 mg kg - 1多奈哌齐可减轻大鼠尼古丁的自我给药。这些作用是强化剂特异性的，而不是由于药物治疗的不良反应，因为反复给药加兰他明和多奈哌齐对蔗糖自我给药、随意进食和异食癖没有影响。反复使用加兰他明（相对于安慰剂）对吸烟的影响也在人类寻求治疗的吸烟者中进行了测试。与安慰剂相比，每天加兰他明治疗两周（8.0 mg（第1周）和16.0 mg（第2周））显着降低了吸烟率以及吸烟满意度和奖励。这项转化性研究表明，在剂量与耐受性和/或不良反应无关的情况下，反复给药乙酰胆碱抑制剂可减少大鼠的尼古丁强化和人类的吸烟行为。
Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg−1 per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg−1 galantamine and 3.0 mg kg−1 donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects.
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影响因子：
2.9
作者：
Geerts, H;Guillaumat, PO;Sachak, S
通讯作者：
Sachak, S
影响因子：
3.9
作者：
Goh, Catherine W.;Aw, Chiu Cheong;Browne, Edward R.
通讯作者：
Browne, Edward R.
影响因子：
--
作者：
Hajek, Peter;McRobbie, Hayden J.;Dhanji, Al-Rehan
通讯作者：
Dhanji, Al-Rehan
影响因子：
3.4
作者：
Kimmey, Blake A.;Rupprecht, Laura E.;Schmidt, Heath D.
通讯作者：
Schmidt, Heath D.
影响因子：
3.2
作者：
Dunbar, F;Zhu, Y;Brashear, HR
通讯作者：
Brashear, HR