Unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro-β-erythroidine in nicotine-tolerant mice.
Unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro-β-erythroidine in nicotine-tolerant mice.
复制标题
尼古丁耐受小鼠对美加明和二氢-β-赤霉素的烟碱乙酰胆碱受体拮抗剂活性的敏感性意外丧失。
DOI：
10.1002/brb3.1581
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发表时间：
2020
影响因子：
3.1
通讯作者：
McMahon,LanceR
中科院分区：
文献类型：
--
作者：
deMoura,FernandoB;Wilkerson,JennyL;McMahon,LanceR
长期以来，人们一直对开发烟碱乙酰胆碱受体（nAChR）拮抗剂与nAChR激动剂（例如，尼古丁替代品）作为辅助戒烟辅助剂。先前的研究表明，每日尼古丁治疗可赋予对尼古丁某些作用的耐受性，以及对其他nAChR激动剂的交叉耐受性。目前的研究评估尼古丁的拮抗作用在多大程度上变化的功能，每日尼古丁treatment.MethodsSchedule-控制的反应和低温被选中的研究，因为他们以前被用来检查尼古丁的药理学，都是敏感的发展尼古丁耐受性。在C57 BL/6 J小鼠中，在每日三次注射1.78 mg/kg尼古丁之前、期间和停止后，检查了尼古丁的心率降低和体温降低效应以及这些效应的拮抗作用。非选择性nAChR拮抗剂美加明和β2 nAChR拮抗剂二氢-β-赤藓定（DHβE）与尼古丁联合研究。结果尼古丁产生心率降低和体温降低效应的ED 50值分别为：每日尼古丁治疗前0.44和0.82 mg/kg，治疗期间1.6和3.2 mg/kg，停止后0.74和1.1 mg/kg。每日尼古丁治疗前，美加明降低反应率和直肠温度。然而，在每日尼古丁期间，美加明（高达5.6 mg/kg）仅降低直肠温度。在每日尼古丁给药前研究时，DHβE（高达5.6 mg/kg）可降低直肠温度，但在长期尼古丁给药期间，该降低消失。在每日尼古丁摄入前后，美加明和DHβE均拮抗尼古丁的心率减慢和体温降低效应;然而，在每日尼古丁摄入期间，美加明和DHβE仅拮抗尼古丁的体温降低效应。结论心率减慢和体温降低效应的差异拮抗作用暗示了nAChR亚型的差异参与。在长期尼古丁治疗期间，美加明和DHβE拮抗尼古丁的能力降低，可能表明其戒烟效果可能因尼古丁耐受性和依赖性而异。
ObjectivesThere is a long‐standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily nicotine treatment confers tolerance to some effects of nicotine, as well as cross‐tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment.MethodsSchedule‐controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development nicotine tolerance. The rate‐decreasing and hypothermic effects of nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist dihydro‐β‐erythroidine (DHβE) were studied in combination with nicotine.ResultsThe ED50values of nicotine to produce rate‐decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily nicotine treatment. Prior to daily nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily nicotine decreased rectal temperature, but that decrease was abolished during chronic nicotine treatment. Mecamylamine and DHβE antagonized the rate‐decreasing and hypothermic effects of nicotine before and after daily nicotine; however, during daily nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of nicotine.ConclusionsThe differential antagonism of rate‐decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize nicotine during chronic nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence.