Journal of Drug and Alcohol Research
Eric J. Nestler
Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1065, New York, NY 10029, USA
Received 2 November 2012; Revised 10 November 2012; Accepted 20 November 2012
ΔFosB is a member of the Fos family of transcription factors. While all other family members are induced rapidly but transiently in response to a host of acute stimuli, ΔFosB is unique in that it accumulates in response to repeated stimulation due to its unusual protein stability.
Such a prolonged induction of ΔFosB, within the brain’s reward regions, has been implicated in animal models of drug addiction, with a wealth of evidence indicating that ΔFosB promotes reward and motivation and serves as a key mechanism of drug sensitization and increased drug self-administration. This has been validated in humans postmortem, with elevated ΔFosB levels seen in reward regions of the addicted brain.
As a transcription factor, ΔFosB produces this behavioral phenotype by regulating the expression of specific target genes. We are identifying such transcriptional targets of ΔFosB by use of a candidate gene approach as well as by use of genome-wide methods. Recent work has analyzed chromatin remodeling—changes in the posttranslational modifications of histones and other nuclear proteins at drug-regulated genes—to delineate the detailed molecular mechanisms by which ΔFosB regulates target gene expression in vivo to mediate drug-induced synaptic, neural, and behavioral plasticity. These studies of ΔFosB are providing new insight into the molecular basis of drug addiction, which is defining a host of new targets for possible therapeutic development.
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