Zhu Hongwen, Lee MoonSook, Agatsuma Soh, Hiroi Noboru
Laboratory of Molecular Psychobiology, Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Hum Mol Genet. 2007 Apr 1;16(7):820-36. doi: 10.1093/hmg/ddm027.
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 of fosB 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 constitutive fosB 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 DeltaFosB in the targets but not at the origins of the mesolimbic and nigrostriatal dopamine pathways; no detectable level of FosB/DeltaFosB 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 of fosB has a pleiotropic influence on the behavioral effects of repeated or prolonged nicotine administration and on stress-related behavioral traits in mice.
人们认为多个基因会影响人类对尼古丁依赖的易感性及其共病行为特征。然而，哪些特定基因导致了这种多效性效应却知之甚少。先前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系统及相关区域转录因子FosB的表达，并且fosB的蛋白质产物会导致可卡因和吗啡的某些行为效应。然而，该基因在尼古丁调节行为和与依赖相关的行为特征中的作用尚不清楚。我们使用组成型fosB基因敲除（KO）小鼠来检验这一假设，即FosB的组成型水平会影响尼古丁调节行为和共病行为特征。在反复或长期给予尼古丁后，而非单次急性给药后，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出现障碍。在野生型小鼠中，反复注射尼古丁而非单次急性注射会增加中脑边缘多巴胺通路和黑质纹状体多巴胺通路靶点而非起源处FosB及其截短变体DeltaFosB的表达；在KO小鼠中未检测到FosB/DeltaFosB水平。在旨在评估行为特征的任务中，与压力水平最小化相比，当压力水平较高时，KO小鼠表现出更明显的行为异常。我们的结果表明，fosB基因的组成型缺失对反复或长期给予尼古丁的行为效应以及小鼠与应激相关的行为特征具有多效性影响。
