Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Neuropsychopharmacology. 2012 Sep;37(10):2310-21. doi: 10.1038/npp.2012.83. Epub 2012 Jun 6.
Current smoking cessation pharmacotherapies have limited efficacy in preventing relapse and maintaining abstinence during withdrawal. Galantamine is an acetylcholinesterase inhibitor that also acts as a positive allosteric modulator of nicotinic acetylcholine receptors. Galantamine has recently been shown to reverse nicotine withdrawal-induced cognitive impairments in mice, which suggests that galantamine may function to prevent relapse in human smokers. However, there are no studies examining whether galantamine administration modulates nicotine self-administration and/or reinstatement of nicotine seeking in rodents. The present experiments were designed to determine the effects of galantamine administration on nicotine taking and reinstatement of nicotine-seeking behavior, an animal model of relapse. Moreover, the effects of galantamine on sucrose-maintained responding and sucrose seeking were also examined to determine whether galantamine's effects generalized to other reinforced behaviors. An inverted U-shaped dose-response curve was obtained when animals self-administered different unit doses of nicotine with the highest responding for 0.03 mg/kg per infusion of nicotine. Acute galantamine administration (5.0 mg/kg, i.p.) attenuated nicotine self-administration when animals were maintained on either a fixed-ratio 5 (FR5) or progressive ratio (PR) schedule of reinforcement. Galantamine administration also attenuated the reinstatement of nicotine-seeking behavior. No significant effects of galantamine on sucrose self-administration or sucrose reinstatement were noted. Acetylcholinesterase inhibitors have also been shown to produce nausea and vomiting in humans. However, at doses required to attenuate nicotine self-administration, no effects of galantamine on nausea/malaise as measured by pica were noted. These results indicate that increased extracellular acetylcholine levels and/or nicotinic acetylcholine receptor stimulation is sufficient to attenuate nicotine taking and seeking in rats and that these effects are reinforcer selective and not due to adverse malaise symptoms such as nausea.
目前的戒烟药物治疗在预防戒断期间的复发和维持戒断方面效果有限。加兰他敏是一种乙酰胆碱酯酶抑制剂，也作为烟碱型乙酰胆碱受体的正变构调节剂。最近的研究表明，加兰他敏可逆转尼古丁戒断引起的小鼠认知障碍，这表明加兰他敏可能有助于预防人类吸烟者的复发。然而，目前还没有研究检查加兰他敏给药是否调节尼古丁自我给药和/或啮齿动物中尼古丁寻求的恢复。本实验旨在确定加兰他敏给药对尼古丁摄取和尼古丁寻求行为恢复的影响，这是一种复发的动物模型。此外，还检查了加兰他敏对蔗糖维持反应和蔗糖寻求的影响，以确定加兰他敏的作用是否扩展到其他强化行为。当动物以 0.03mg/kg/次的不同单位剂量自我给予尼古丁时，获得了一个倒 U 形剂量反应曲线。急性加兰他敏给药（5.0mg/kg，ip）在动物维持固定比率 5（FR5）或递增比率（PR）强化方案时减弱了尼古丁的自我给药。加兰他敏给药也减弱了尼古丁寻求行为的恢复。加兰他敏对蔗糖自我给药或蔗糖恢复没有显著影响。乙酰胆碱酯酶抑制剂也已被证明会在人类中引起恶心和呕吐。然而，在减弱尼古丁自我给药所需的剂量下，加兰他敏对通过嗜食测量的恶心/不适没有影响。这些结果表明，增加细胞外乙酰胆碱水平和/或烟碱型乙酰胆碱受体刺激足以减弱大鼠的尼古丁摄取和寻求，并且这些作用是强化剂选择性的，而不是由于恶心等不良不适症状。
