Partial and full deletion of nicotinic acetylcholine receptor α4 and β2 subunits reduces sensitivity to acute nicotine administration and development of tolerance following chronic nicotine administration.
Partial and full deletion of nicotinic acetylcholine receptor α4 and β2 subunits reduces sensitivity to acute nicotine administration and development of tolerance following chronic nicotine administration.
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部分和完全删除烟碱乙酰胆碱受体α4 和β2 亚基可降低对急性尼古丁给药的敏感性和慢性尼古丁给药后耐受性的发展。
DOI：
10.1097/fbp.0000000000000575
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发表时间：
2020
影响因子：
1.6
通讯作者：
Collins,AllanC
中科院分区：
文献类型：
--
作者：
Marks,MichaelJ;Loetz,Esteban;Ortiz,NickC;Herder,PenelopeA;Collins,AllanC
烟碱胆碱能受体 (nAChR) 亚基的多样性是对尼古丁复杂反应的基础。 α4 和 β2 亚基（在大脑中表达最广泛）的表达存在差异，在长期尼古丁治疗（0、0.25、1.0 和 4.0 mg/kg/h）后，评估了小鼠对 Y 迷宫交叉和后方急性尼古丁给药的反应、旷场运动和体温。 α4、β2 或两个 nAChR 亚基的缺失或部分缺失降低了小鼠对急性尼古丁给药的敏感性。这种敏感性的降低是基因剂量依赖性的。 α4 亚基表达的修饰比β2 亚基表达的修饰引起更大的敏感性降低。任何基因型的小鼠在接受 0.25 mg/kg/h 尼古丁长期治疗后均未观察到可测量的耐受性。用 1.0 mg/kg/h 治疗后观察到适度的耐受性。用 4.0 mg/kg/h 治疗后观察到更大的耐受性。小鼠的耐受程度因基因型而异：野生型（α4++ 和 β2++）对所有四项测试都产生了可测量的耐受性。杂合子（α4+−、β2+− 和 α4+−/β2+−）仅对 Y 迷宫穿越和体温产生耐受性。无效突变体（α4−− 和 β2−−）没有变得耐受。然而，在用 4.0 mg/kg/h 尼古丁长期治疗后，野生型、α4+− 和 α4−− 小鼠在急性施用 0.5 mg/kg 尼古丁后表现出 Y 迷宫穿越增加，这可能反映了 α6β2*-nAChR 的活性。这些结果证实了 α4 和 β2 nAChR 亚基在介导尼古丁对小鼠运动和体温的急性和慢性影响中的重要性。
The diversity of nicotinic cholinergic receptor (nAChR) subunits underlies the complex responses to nicotine. Mice differing in the expression of α4 and β2 subunits, which are most widely expressed in brain, were evaluated for the responses to acute nicotine administration on Y-maze crossings and rears, open-field locomotion and body temperature following chronic treatment with nicotine (0, 0.25, 1.0 and 4.0 mg/kg/h). Deletion or partial deletion of the α4, β2 or both nAChR subunits reduced the sensitivity of mice to acute nicotine administration. This reduced sensitivity was gene dose-dependent. Modification of α4 subunit expression elicited a greater reduction in sensitivity than the modification of β2 subunit expression. No measurable tolerance was observed for mice of any genotype following chronic treatment with 0.25 mg/kg/h nicotine. Modest tolerance was noted following treatment with 1.0 mg/kg/h. Greater tolerance was observed following treatment with 4.0 mg/kg/h. The extent of tolerance differed among the mice depending on genotype: wild-type (α4++ and β2++) developed measurable tolerance for all four tests. Heterozygotes (α4+−, β2+− and α4+−/β2+−) developed tolerance for only Y-maze crossings and body temperature. Null mutants (α4−− and β2−−) did not become tolerant. However, following chronic treatment with 4.0 mg/kg/h nicotine, wild type, α4+− and α4−− mice displayed increased Y-maze crossings following acute administration of 0.5 mg/kg nicotine that may reflect the activity of α6β2*-nAChR. These results confirm the importance of the α4 and β2 nAChR subunits in mediating acute and chronic effects of nicotine on locomotion and body temperature in the mouse.