Donepezil, an acetylcholinesterase inhibitor, attenuates nicotine self-administration and reinstatement of nicotine seeking in rats
Donepezil, an acetylcholinesterase inhibitor, attenuates nicotine self-administration and reinstatement of nicotine seeking in rats
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DOI：
10.1111/adb.12014
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发表时间：
2014-07-01
影响因子：
3.4
通讯作者：
Schmidt, Heath D.
中科院分区：
文献类型：
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作者：
Kimmey, Blake A.;Rupprecht, Laura E.;Schmidt, Heath D.
尼古丁渴望和认知障碍是尼古丁戒断的核心症状，预示着戒烟者的复发。目前的戒烟药物治疗在预防复发和戒断期间保持戒烟的有效性有限。多奈哌齐是一种乙酰胆碱酯酶抑制剂，先前已显示可改善健康非寻求治疗的吸烟者的认知能力。然而，目前还没有研究检查多奈哌齐对啮齿动物尼古丁自我给药和/或尼古丁寻求行为恢复的影响。本实验旨在确定急性多奈哌齐给药对尼古丁摄入和尼古丁寻求行为恢复的影响，这是一种人类戒烟者复发的动物模型。此外，我们还研究了急性多奈哌齐给药对蔗糖自我给药和蔗糖寻找的影响，以确定多奈哌齐的作用是否会推广到其他强化行为。急性多奈哌齐给药（1.0或3.0 mg/kg, i.p.p）会减弱尼古丁，但不会以固定比例5的强化方式自我给药。多奈哌齐也剂量依赖性地减弱了尼古丁和蔗糖寻求行为的恢复。多奈哌齐治疗人类常见的不良反应是恶心和呕吐。然而，在减少啮齿动物尼古丁自我给药所需的剂量下，没有观察到多奈哌齐对异食癖测量的恶心/不适的影响。总的来说，这些结果表明，细胞外乙酰胆碱水平的增加足以减轻大鼠对尼古丁的摄入和寻求，而且这些影响不是由于恶心等不良不适症状。
Nicotine craving and cognitive impairments represent core symptoms of nicotine withdrawal and predict relapse in abstinent smokers. Current smoking cessation pharmacotherapies have limited efficacy in preventing relapse and maintaining abstinence during withdrawal. Donepezil is an acetylcholinesterase inhibitor that has been shown previously to improve cognition in healthy non-treatment-seeking smokers. However, there are no studies examining the effects of donepezil on nicotine self-administration and/or the reinstatement of nicotine-seeking behavior in rodents. The present experiments were designed to determine the effects of acute donepezil administration on nicotine taking and the reinstatement of nicotine-seeking behavior, an animal model of relapse in abstinent human smokers. Moreover, the effects of acute donepezil administration on sucrose self-administration and sucrose seeking were also investigated in order to determine whether donepezil's effects generalized to other reinforced behaviors. Acute donepezil administration (1.0 or 3.0 mg/kg, i.p.) attenuated nicotine, but not sucrose self-administration maintained on a fixed-ratio 5 schedule of reinforcement. Donepezil administration also dose-dependently attenuated the reinstatement of both nicotine-and sucrose-seeking behaviors. Commonly reported adverse effects of donepezil treatment in humans are nausea and vomiting. However, at doses required to attenuate nicotine self-administration in rodents, no effects of donepezil on nausea/malaise as measured by pica were observed. Collectively, these results indicate that increased extracellular acetylcholine levels are sufficient to attenuate nicotine taking and seeking in rats and that these effects are not due to adverse malaise symptoms such as nausea.