Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats
Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats
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DOI：
10.1007/s00213-003-1426-x
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发表时间：
2003-06-01
影响因子：
3.4
通讯作者：
Terry, P
中科院分区：
文献类型：
--
作者：
Desai, RI;Barber, DJ;Terry, P
理由：先前的工作已经证明了尼古丁和可卡因的区别刺激效应之间的不对称交叉概括：尼古丁完全替代可卡因，而可卡因仅部分替代尼古丁。造成这两种药物之间相似性和差异的因素仍不清楚。目的：该研究测试了多巴胺能和/或胆碱能机制在尼古丁和可卡因的区别刺激作用中的参与情况。方法：训练一组大鼠区分可卡因（8.9 mg/kg）和盐水，另外两组大鼠训练区分尼古丁（0.1 mg/kg）和盐水。结果：在接受可卡因训练的大鼠中，在研究的胆碱能激动剂中，只有尼古丁（0.01-0.56 mg/kg）产生完全的、剂量相关的替代；去甲尼古丁（1-5.6 mg/kg）仅部分替代，而山梗碱（2.71-15.34 mg/kg）和毛果芸香碱（0.26-2.55 mg/kg）未能产生任何可卡因适当的反应。烟碱拮抗剂美加明（1-5.6 mg/kg）未能阻断可卡因的歧视性刺激作用。多巴胺拮抗剂顺氟哌噻吨 (cis-flupentixol) (0.48 mg/kg) 阻断尼古丁对可卡因的替代。在尼古丁训练的大鼠中，多巴胺摄取阻滞剂可卡因、安非他酮和诺米芬辛（0.2-26.1 mg/kg）各自仅部分替代尼古丁，顺式氟哌噻吨（0.48-0.86 mg/kg）拮抗尼古丁的辨别刺激作用。结论：尼古丁完全替代可卡因，因为它对多巴胺传递有影响，而不是因为可卡因的辨别刺激作用包含胆碱能成分。用尼古丁替代可卡因可能更多地依赖于尼古丁诱导的多巴胺释放，而不是尼古丁训练的辨别刺激；在用尼古丁或可卡因进行急性和反复治疗后，可能会出现不同的多巴胺能受累。
Rationale: Previous work has demonstrated asymmetrical cross-generalization between the discriminative stimulus effects of nicotine and cocaine: nicotine fully substitutes for cocaine, whereas cocaine only partially substitutes for nicotine. The factors responsible for the similarities and differences between the two drugs remain unclear. Objective: The study tested the involvement of dopaminergic and/or cholinergic mechanisms in the discriminative stimulus effects of nicotine and cocaine. Methods: One set of rats was trained to discriminate cocaine (8.9 mg/kg) from saline, and two other sets of rats were trained to discriminate nicotine (0.1 mg/kg) from saline. Results: In cocaine-trained rats, among the cholinergic agonists studied only nicotine (0.01-0.56 mg/kg) produced full, dose-related substitution; nornicotine (1-5.6 mg/kg) substituted only partially, and lobeline (2.71-15.34 mg/kg) and pilocarpine (0.26-2.55 mg/kg) failed to engender any cocaine-appropriate responding. The nicotinic antagonist mecamylamine (1-5.6 mg/kg) failed to block cocaine's discriminative stimulus effects. The dopamine antagonist cis-flupentixol (0.48 mg/kg) blocked the substitution of nicotine for cocaine. In nicotine-trained rats, the dopamine uptake blockers cocaine, bupropion and nomifensine (0.2-26.1 mg/kg) each substituted only partially for nicotine, and cis-flupentixol (0.48-0.86 mg/kg) antagonized the discriminative stimulus effects of nicotine. Conclusions: Nicotine fully substitutes for cocaine because of its effects on dopamine transmission, and not because the discriminative stimulus effects of cocaine incorporate a cholinergic component. Substitution of nicotine for cocaine may depend more on nicotine-induced dopamine release than does the nicotine-trained discriminative stimulus; there may be differential dopaminergic involvement after acute and repeated treatment with nicotine or cocaine.