FosB mutant mice: Loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects
FosB mutant mice: Loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects
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DOI：
10.1073/pnas.94.19.10397
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发表时间：
1997-09-16
影响因子：
11.1
通讯作者：
Nestler, EJ
中科院分区：
文献类型：
--
作者：
Hiroi, N;Brown, JR;Nestler, EJ
长期接触可卡因会导致显著的、持久的行为变化，这是成瘾状态的特征。纹状体，包括伏隔核和尾核，是这些活动的重要基础。我们之前已经证明，长期服用可卡因可在纹状体中诱导35-37 kDa的持久性fos相关蛋白。在本研究中，我们用fosB突变小鼠检测了这些fos相关蛋白的身份和功能作用。这些小鼠的纹状体完全缺乏基础水平的35- 37 kda fos相关蛋白，以及它们在长期可卡因管理下的诱导作用，这种缺乏与对可卡因的增强行为反应有关：与野生型幼崽相比，fosB突变小鼠在初始可卡因暴露时表现出过度的运动激活，以及对较低剂量可卡因的强大条件位置偏好。这些结果证实了Fos相关蛋白是fosB基因的产物（特别是Delta fosB亚型），并表明fosB基因产物的转录调控在可卡因诱导的行为反应中起着关键作用。这一发现表明Fos家族成员蛋白在滥用药物的行为反应中起着功能性作用，并暗示fosB基因产物是可卡因滥用的重要决定因素。
Chronic exposure to cocaine leads to prominent, long-lasting changes in behavior that characterize a state of addiction. The striatum, including the nucleus accumbens and caudoputamen, is an important substrate for these actions. We previously have shown that long-lasting Fos-related proteins of 35-37 kDa are induced in the striatum by chronic cocaine administration. In the present study, the identity and functional role of these Fos-related proteins were examined using fosB mutant mice. The striatum of these mice completely lacked basal levels of the 35- to 37-kDa Fos-related proteins as well as their induction by chronic cocaine administration, This deficiency was associated with enhanced behavioral responses to cocaine: fosB mutant mice showed exaggerated locomotor activation in response to initial cocaine exposures as well as robust conditioned place preference to a lower dose of cocaine, compared with wild-type littermates. These results establish the long-lasting Fos-related proteins as products of the fosB gene (specifically Delta FosB isoforms) and suggest that transcriptional regulation by fosB gene products plays a critical role in cocaine-induced behavioral responses, This finding demonstrates that a Fos family member protein plays a functional role in behavioral responses to drugs of abuse and implicates fosB gene products as important determinants of cocaine abuse.