ΔFosB:: A sustained molecular switch for addiction

被引:464
作者
Nestler, EJ
Barrot, M
Self, DW
机构
[1] Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Ctr, Ctr Basic Neurosci, Dallas, TX 75390 USA
关键词
D O I
10.1073/pnas.191352698
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The longevity of some of the behavioral abnormalities that characterize drug addiction has suggested that regulation of neural gene expression may be involved in the process by which drugs of abuse cause a state of addiction. Increasing evidence suggests that the transcription factor Delta FosB represents one mechanism by which drugs of abuse produce relatively stable changes in the brain that contribute to the addiction phenotype. Delta FosB, a member of the Fos family of transcription factors, accumulates within a subset of neurons of the nucleus accumbens and dorsal striatum (brain regions important for addiction) after repeated administration of many kinds of drugs of abuse. Similar accumulation of Delta FosB occurs after compulsive running, which suggests that Delta FosB may accumulate in response to many types of compulsive behaviors. Importantly, Delta FosB persists in neurons for relatively long periods of time because of its extraordinary stability. Therefore, Delta FosB represents a molecular mechanism that could initiate and then sustain changes in gene expression that persist long after drug exposure ceases. Studies in inducible transgenic mice that overexpress either Delta FosB or a dominant negative inhibitor of the protein provide direct evidence that Delta FosB causes increased sensitivity to the behavioral effects of drugs of abuse and, possibly, increased drug seeking behavior. This work supports the view that Delta FosB functions as a type of sustained "molecular switch" that gradually converts acute drug responses into relatively stable adaptations that contribute to the long-term neural and behavioral plasticity that underlies addiction.
引用
收藏
页码:11042 / 11046
页数:5
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