Serotonergic mechanism underlying tranylcypromine enhancement of nicotine self-administration.
Serotonergic mechanism underlying tranylcypromine enhancement of nicotine self-administration.
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反苯环丙明增强尼古丁自我给药的血清素机制。
DOI：
10.1002/syn.20864
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
Leslie,FrancesM
中科院分区：
文献类型：
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作者：
Villégier,Anne-Sophie;Belluzzi,JamesD;Leslie,FrancesM
虽然尼古丁通常被认为是烟草的主要精神活性成分，但越来越多的证据表明非尼古丁化合物在吸烟强化中的重要性。单胺氧化酶（MAO）抑制是吸烟的主要后果，而MAO抑制剂（如反苯环丙胺）会增加尼古丁的强化作用。反苯环丙胺具有多种药理作用，在给药后立即增加单胺释放数小时，并阻断MAO活性数天。为了评估这两种作用的相对作用，对成年雄性大鼠进行了连续每日3小时的尼古丁自我给药（3 μg kg− 1 inj −1，i. v.）给予反苯环丙胺（3 mg kg-1）后20或1 h。这两种范例都显示出对MAO活性产生高度显著的抑制。然而，尽管动物在试验前1小时用反苯环丙胺预处理时容易获得自我给药，但在较长的预处理间隔内不会获得自我给药。当反苯环丙胺预处理间隔转换为第4天试验前1小时时，这些动物确实立即获得尼古丁自我给药，表明MAO抑制剂的急性效应是增强尼古丁强化的原因。有几条证据表明5-羟色胺（5-HT）是这种增强作用的介质：（1）5-HT 2受体拮抗剂利坦色林和酮色林可阻断Trancyclypromine增强的尼古丁增强作用;（2）对氯苯丙胺（PCA），一种5-HT抑制剂，也可增强MAO活性受到抑制的动物的尼古丁自我给药;（3）反苯环丙胺预处理可增加PCA诱导的丘脑外侧核5-HT溢出。这些发现表明，MAO抑制增强了尼古丁能传递，这在尼古丁的强化作用中起着关键作用。Synapse，2011年。© 2010 Wiley利斯公司
Although nicotine is generally considered to be the main psychoactive component of tobacco, growing evidence highlights the importance of nonnicotine compounds in smoking reinforcement. Monoamine oxidase (MAO) inhibition is a major consequence of smoking and MAO inhibitors, such as tranylcypromine, increase nicotine reinforcement. Tranylcypromine has multiple pharmacological effects, increasing monoamine release for a few hours immediately after its administration and blocking MAO activity for several days. To assess the relative role of these two actions, adult male rats were tested in consecutive daily 3‐h sessions for self‐administration of nicotine (3 μg kg−1inj−1, i.v.) either 20 or 1 h following administration of tranylcypromine (3 mg kg−1). Both paradigms were shown to produce highly significant inhibition of MAO activity. However, whereas animals readily acquired self‐administration when pretreated with tranylcypromine 1 h prior to testing, they did not with the longer pretreatment interval. Such animals did immediately acquire nicotine self‐administration when the tranylcypromine pretreatment interval was switched to 1 h prior to testing on Day 4, indicating that an acute effect of the MAO inhibitor was responsible for enhanced nicotine reinforcement. Several lines of evidence implicate serotonin (5‐HT) as the mediator of this enhancement: (1) Tranyclypromine‐enhanced nicotine reinforcement was blocked by the 5‐HT2receptor antagonists, ritanserin and ketanserin; (2) parachloroamphetamine (PCA), a 5‐HT releaser, also enhanced nicotine self‐administration in animals in which MAO activity was inhibited; (3) pretreatment with tranylcypromine increased PCA‐induced 5‐HT overflow in the nucleus accumbens. These findings suggest that MAO inhibition enhances serotonergic transmission, which serves a critical role in the reinforcing effects of nicotine. Synapse, 2011. © 2010 Wiley‐Liss, Inc.