Intravenous nicotine self-administration and cue-induced reinstatement in mice: effects of nicotine dose, rate of drug infusion and prior instrumental training.
Intravenous nicotine self-administration and cue-induced reinstatement in mice: effects of nicotine dose, rate of drug infusion and prior instrumental training.
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DOI：
10.1016/j.neuropharm.2011.05.012
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发表时间：
2011-09
影响因子：
4.7
通讯作者：
Kenny PJ
中科院分区：
文献类型：
--
作者：
Fowler CD;Kenny PJ
在实验动物中，静脉注射尼古丁自我给药是尼古丁强化的最直接措施，但这一程序已被证明难以在小鼠中建立。我们发现，C57BL6/J小鼠对尼古丁的稳定反应是由以下因素促进的：先前的食物奖励工具训练、小鼠在获得更高剂量之前初始暴露于较低单位剂量的尼古丁（0.03 mg/kg/输注）、较慢的给药速度（3秒与1秒输注）、每日测试计划的一致性以及测试过程中的低外来噪音。在这些条件下，我们发现，在固定比例5超时20秒（FR5TO20）强化计划下，小鼠按杠杆按压尼古丁（0.03-0.4 mg/kg/输注，60分钟试验时间）消耗的药物呈倒“U”型剂量-反应曲线。当活跃/不活跃的杠杆分配被逆转时，小鼠将它们的反应切换到先前未强化的杠杆上，继续获得尼古丁注入。尼古丁乙酰胆碱受体（nAChR）拮抗剂甲胺可降低小鼠对尼古丁的反应，但不影响食物奖励，这证实了nAChR可调节小鼠对尼古丁的自我给药。当单独注射尼古丁时，与尼古丁配对的提示光不支持反应，进一步证实小鼠对药物有选择性反应。当尼古丁注入和提示光被停止时，寻求尼古丁的反应就会消失，而暴露在提示光下则会恢复反应。最后，没有事先进行食物训练的小鼠在FR5TO20计划下获得了对尼古丁的稳定反应，但需要更多的训练次数。这些数据表明，尼古丁在小鼠中是一种有效的强化剂，并建立了小鼠可靠自我给药的条件。
Intravenous nicotine self-administration is the most direct measure of nicotine reinforcement in laboratory animals, but this procedure has proven difficult to establish in mice. We found that stable responding for nicotine in C57BL6/J mice was facilitated by prior instrumental training for food reward, initial exposure of mice to a lower unit dose of nicotine (0.03 mg/kg/infusion) before access to higher doses, a slower rate of drug delivery (3-sec versus 1-sec infusion), consistency in schedule of daily testing, and low extraneous noise during testing. Under these conditions, we found that mice lever-pressing for nicotine (0.03–0.4 mg/kg/infusion; 60-min test sessions) under a fixed-ratio 5 time-out 20-sec (FR5TO20) reinforcement schedule consumed the drug according to an inverted ‘U’-shaped dose-response curve. Mice switched their responding onto a previously non-reinforced lever to continue earning nicotine infusions when the active/inactive lever assignment was reversed. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine decreased responding for nicotine, but not food rewards, verifying that nAChRs regulate nicotine self-administration in mice. The cue-light paired with nicotine delivery did not support responding when delivered independently of nicotine infusions, further verifying that mice responded selectivity for the drug. Nicotine-seeking responses extinguished when nicotine infusions and the cue-light were withheld, and exposure to the cue-light reinstated responding. Finally, mice without prior instrumental food training acquired stable responding for nicotine under the FR5TO20 schedule, but required a greater number of sessions. These data demonstrate that nicotine is an effective reinforcer in mice and establish conditions under which the drug is reliably self-administered by mice.