The dorsal raphe nucleus is a crucial structure mediating nicotine's anxiolytic effects and the development of tolerance and withdrawal responses
The dorsal raphe nucleus is a crucial structure mediating nicotine's anxiolytic effects and the development of tolerance and withdrawal responses
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DOI：
10.1007/s002130100681
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发表时间：
2001-04-01
影响因子：
3.4
通讯作者：
File, SE
中科院分区：
文献类型：
--
作者：
Cheeta, S;Irvine, EE;File, SE
理由：吸烟者经常报告他们从吸烟中获得减少焦虑（抗焦虑）的效果。这可能是导致尼古丁依赖的一个因素。目的：本研究的目的是探讨中缝背核（DRN）在介导尼古丁的急性抗焦虑作用，对这种作用的耐受性的发展和慢性尼古丁戒断时观察到的致焦虑反应中的作用。研究方法：使用焦虑的社交互动测试来研究DRN输注后一系列剂量的（-）-尼古丁（2.5-4000 ng）的作用。以及联合应用特异性5-HT 1A受体拮抗剂WAY 100635是否能拮抗尼古丁的抗焦虑作用。Wt然后检查在每天六次皮下（s.c.）（-）-尼古丁（0.1 mg/kg）。最后，我们研究了s.c.或DRN内（-）-尼古丁可拮抗尼古丁处理7 d后72 h的焦虑反应。结果如下：DRN中的急性尼古丁给药产生剂量相关效应;低剂量（2.5-10 ng）诱导抗焦虑效应，中等剂量（100-1000 ng）行为沉默，高剂量（4 μ g）给药后观察到致焦虑效应。与行为无活性剂量的WAY 100635（200 ng）联合给药可逆转（-）-尼古丁（5 ng）的抗焦虑作用。在用s.c. 0.1 mg/kg/天（-）-尼古丁，在DRN中对其抗焦虑作用产生耐受性。长期给药后72小时停药的大鼠显示出焦虑反应，可通过皮下注射（-）-尼古丁逆转。(0.1 mg/kg）或DRN（5 ng）。结论：因此，目前的研究结果表明，DRN起着重要的作用，在介导的急性尼古丁对焦虑的影响，在社会互动测试中测量，和抗焦虑作用介导的体树突5-HT 1A自身受体的激活。DRN还涉及介导对尼古丁抗焦虑作用的耐受性的发展，并且因为在戒断慢性尼古丁后72小时存在致焦虑反应，这表明对抗性代偿机制介导耐受性。
Rationale: Smokers frequently report that they obtain anxiety-reducing (anxiolytic) effects from smoking. and this may be one factor which contributes to nicotine dependence. Objective: The aim of this study was to investigate the role of the dorsal raphe nucleus (DRN) in mediating the acute anxiolytic effect of nicotine, the development of tolerance to this effect and the anxiogenic response observed on withdrawal from chronic nicotine. Methods: The social interaction test of anxiety was used to investigate the effects of a range of doses of (-)-nicotine (2.5-4000 ng) following DRN infusion. and whether co-administration of the specific 5-HT1A receptor antagonist WAY 100635 could antagonise the anxiolytic action of nicotine. Wt then examined the effects of intra-DRN nicotine (2.5-7 ng) following six daily injections of subcutaneous (s.c.) (-)-nicotine (0.1 mg/kg). Finally, we examined whether s.c. or intra-DRN (-)-nicotine could antagonise the anxiogenic response seen 72 h after the termination of 7 days of nicotine treatment. Results: Acute nicotine administration into the DRN produced dose-related effects; low doses (2.5-10 ng) induced an anxiolytic effect, intermediate doses were behaviourally silent (100-1000 ng), and an anxiogenic effect was seen following administration of a high dose (4 mug). The anxiolytic effect of (-)-nicotine (5 ng) was reversed by co-administration of a behaviourally inactive dose of WAY 100635 (200 ng). Following 6 days of treatment with s.c. 0.1 mg/kg per day (-)-nicotine, tolerance developed to its anxiolytic action in the DRN. Rats withdrawn for 72 h following this chronic treatment showed an anxiogenic response which was reversed by (-)-nicotine injected s.c. (0.1 mg/kg) or into the DRN (5 ng). Conclusions: The present findings therefore suggest that the DRN plays an important role in mediating the acute effects of nicotine on anxiety, as measured in the social interaction test, and that the anxiolytic effect is mediated by activation of somatodendritic 5-HT1A auto-receptors. The DRN is also concerned with mediating the development of tolerance to nicotine's anxiolytic effects and because there is an anxiogenic response 72 h after withdrawal from chronic nicotine, this suggests that an oppositional, compensatory mechanism is mediating the tolerance.