Pleiotropic impact of constitutive fosB inactivation on nicotine-induced behavioral alterations and stress-related traits in mice.
Pleiotropic impact of constitutive fosB inactivation on nicotine-induced behavioral alterations and stress-related traits in mice.
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fosB 组成型失活对尼古丁诱导的小鼠行为改变和应激相关性状的多效性影响。
DOI：
10.1093/hmg/ddm027
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发表时间：
2007
影响因子：
3.5
通讯作者：
Hiroi,Noboru
中科院分区：
文献类型：
--
作者：
Zhu,Hongwen;Lee,MoonSook;Agatsuma,Soh;Hiroi,Noboru
多个基因被认为既影响人类对尼古丁依赖的易感性，也影响其共病行为特征。然而，哪些特定基因对这种多效性效应起作用还知之甚少。以往的啮齿动物研究表明，许多成瘾物质和应激刺激会增加边缘及相关区域转录因子FosB的表达，并且FosB的蛋白产物与可卡因和吗啡的某些行为效应有关。然而，该基因在尼古丁调节行为和依赖相关行为特征中的作用尚不清楚。我们用构成FosB基因敲除(KO)小鼠检验了这样的假设，即构成水平的FosB影响尼古丁调节的行为和共病的行为特征。反复或长期给予尼古丁，但不是单一的急性给药，KO小鼠在条件性位置偏爱、口服尼古丁摄取和运动抑制方面受到损害。在野生型小鼠中，重复注射尼古丁，但不是单一的急性注射，增加了靶标中FosB及其截断的突变体ΔFosB的表达，但不增加中边缘和黑质纹状体多巴胺通路的起点；在KO小鼠中没有检测到FosB/ΔFosB的水平。在旨在评估行为特征的任务中，当压力水平较高时，KO小鼠表现出比压力最小时更明显的行为异常。我们的结果表明，结构性缺失的osB对重复或延长尼古丁给药的行为效应以及对应激相关的行为特征有多方面的影响。
Multiple genes are thought to influence both susceptibility to nicotine dependence and its comorbid behavioral traits in humans. However, which specific genes contribute to this pleiotropic effect is poorly understood. Previous rodent studies have shown that many addictive substances and stressful stimuli increase the expression of the transcription factor FosB in limbic and associated regions and that the protein products offosB contribute to certain behavioral effects of cocaine and morphine. However, the role of this gene in nicotine-regulated behaviors and dependence-related behavioral traits is unknown. We tested the hypothesis that a constitutive level of FosB affects nicotine-regulated behaviors and comorbid behavioral traits using constitutivefosB knockout (KO) mice. Following repeated or prolonged nicotine administration, but not a single acute administration, KO mice were impaired in conditioned place preference, oral nicotine intake and motor suppression. In wild-type mice, repeated nicotine injections, but not a single acute injection, increased the expression of FosB and its truncated variant ΔFosB in the targets but not at the origins of the mesolimbic and nigrostriatal dopamine pathways; no detectable level of FosB/ΔFosB was found in KO mice. In tasks designed to assess behavioral traits, KO mice exhibited more pronounced behavioral abnormalities when stress levels were high than when they were minimized. Our results suggest that the constitutive absence offosB has a pleiotropic influence on the behavioral effects of repeated or prolonged nicotine administration and on stress-related behavioral traits in mice.