Review. Transcriptional mechanisms of addiction: role of DeltaFosB.
Regulation of gene expression is considered a plausible mechanism of drug addiction, given the stability of behavioural abnormalities that define an addicted state. Among many transcription factors known to influence the addiction process, one of the best characterized is DeltaFosB, which is induced in the brain's reward regions by chronic exposure to virtually all drugs of abuse and mediates sensitized responses to drug exposure. Since DeltaFosB is a highly stable protein, it represents a mechanism by which drugs produce lasting changes in gene expression long after the cessation of drug use. Studies are underway to explore the detailed molecular mechanisms by which DeltaFosB regulates target genes and produces its behavioural effects. We are approaching this question using DNA expression arrays coupled with the analysis of chromatin remodelling--changes in the posttranslational modifications of histones at drug-regulated gene promoters--to identify genes that are regulated by drugs of abuse via the induction of DeltaFosB and to gain insight into the detailed molecular mechanisms involved. Our findings establish chromatin remodelling as an important regulatory mechanism underlying drug-induced behavioural plasticity, and promise to reveal fundamentally new insight into how DeltaFosB contributes to addiction by regulating the expression of specific target genes in brain reward pathways.
Nestler
Eric J
EJ
Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA. eric.nestler@mssm.edu
D016739:Behavior, Addictive / Q000503:physiopathology*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D013287:Illicit Drugs / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012201:Reward; D019966:Substance-Related Disorders / Q000503:physiopathology*
D013287:Illicit Drugs; D016760:Proto-Oncogene Proteins c-fos