Delta FosB: A sustained molecular switch for addiction

The longevity of some of the behavioral abnormalities that characterize dru g 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 repr esents one mechanism by which drugs of abuse produce relatively stable chan ges in the brain that contribute to the addiction phenotype. Delta FosB, a member of the Fos family of transcription factors, accumulates within a sub set of neurons of the nucleus accumbens and dorsal striatum (brain regions important for addiction) after repeated administration of many kinds of dru gs of abuse. Similar accumulation of Delta FosB occurs after compulsive run ning, which suggests that Delta FosB may accumulate in response to many typ es of compulsive behaviors. Importantly, Delta FosB persists in neurons for relatively long periods of time because of its extraordinary stability. Th erefore, Delta FosB represents a molecular mechanism that could initiate an d then sustain changes in gene expression that persist long after drug expo sure ceases. Studies in inducible transgenic mice that overexpress either D elta FosB or a dominant negative inhibitor of the protein provide direct ev idence that Delta FosB causes increased sensitivity to the behavioral effec ts of drugs of abuse and, possibly, increased drug seeking behavior. This w ork supports the view that Delta FosB functions as a type of sustained "mol ecular switch" that gradually converts acute drug responses into relatively stable adaptations that contribute to the long-term neural and behavioral plasticity that underlies addiction.