Genetic matters: thirty years of progress using mouse models in nicotinic research.
Genetic matters: thirty years of progress using mouse models in nicotinic research.
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DOI：
10.1016/j.bcp.2013.05.021
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发表时间：
2013-10-15
影响因子：
5.8
通讯作者：
Marks MJ
中科院分区：
文献类型：
--
作者：
Marks MJ
这一研究更新总结了三十年来关于基因对尼古丁急性或慢性给药反应的影响的研究。早期的研究表明，各种近亲交配的小鼠对这种药物的效果有不同的敏感性。经典的遗传分析证实，尼古丁对运动、体温和癫痫发作的影响是可遗传的。运动和低温效应与尼古丁结合位点密度之间的显著负相关表明，差异表达的α-4-β-神经元型烟碱乙酰胆碱受体(NAChR)介导了这种遗传变异。随后对α4和β2nAChR缺失(敏感度降低)和功能突变获得(敏感度增加)的研究支持α4β2*nAChR亚型的作用。然而，零突变小鼠仍然对尼古丁有反应，这表明其他nAChR亚型也介导了这些反应。对尼古丁初始敏感性不同的小鼠在慢性治疗后的耐受性发展也不同：那些最初对尼古丁更敏感的小鼠在治疗剂量比不敏感的小鼠更容易产生耐受性，这表明耐受性是对尼古丁影响的适应性反应。相反，小鼠对脉冲前抑制声惊厥反应的敏感性与α7-nAChR的表达相关。虽然nAChR表达和功能的遗传变异性是导致对尼古丁反应差异的一个重要因素，但阿片、谷氨酸和大麻素受体等的活性改变也改变了尼古丁的敏感性，这一观察结果强化了尼古丁反应的遗传学比nAChRs的差异更复杂的假设。
This Research Update summarizes thirty years of studies on genetic influences on responses to the acute or chronic administration of nicotine. Early studies established that various inbred mice are differentially sensitive to the effects of the drug. Classical genetic analyses confirmed that nicotine effects on locomotion, body temperature and seizures are heritable. A significant inverse correlation between the locomotor and hypothermic effects and the density of nicotine binding sites suggested that differential expression α4β2-neuronal nicotinic acetylcholine receptor (nAChR) mediated some of this genetic variability. Subsequent studies with α4 and β2 nAChR null (decreased sensitivity) and gain of function mutants (increased sensitivity) supports the role of the α4β2*nAChR subtype. However, null mutant mice still respond to nicotine, indicating that other nAChR subtypes also mediate these responses. Mice differing in initial sensitivity to nicotine also differ in tolerance development following chronic treatment: Those mice that are initially more sensitive to nicotine develop tolerance at lower treatment doses than less sensitive mice, indicating that tolerance is an adaptive response to the effects of nicotine.. In contrast, the sensitivity of mice to pre-pulse inhibition of acoustic startle response is correlated with the expression of α7-nAChR. While genetic variability in nAChR expression and function is an important factor contributing to differences in response to nicotine, the observations that altered activity of opioid, glutamate, and cannabinoid receptors among others also change nicotine sensitivity reinforces the proposal that the genetics of nicotine response is more complex than differences in nAChRs.
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