Transcriptional mechanisms of addiction: role of ΔFosB

Abstract

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 DFosB, 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 DFosB 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 DFosB 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 DFosB 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 DFosB contributes to addiction by regulating the expression of specific target genes in brain reward pathways.

Effect of chronic heroin and cocaine administration on global DNA methylation in brain and liver

“…There is now substantial evidence that supports the involvement of epigenetic mechanisms in gene expression alterations related to psychiatric disorders, including drug addiction (Haycock, 2009;Kalsi et al, 2009;Kovatsi et al, 2011;Lutz, 2008;Malvaez et al, 2009;McQuown and Wood, 2010;Nestler, 2008;Nestler, 2008, 2009;Tsankova et al, 2007). Drug abuse, as an environmental stimulus, can trigger epigenetic changes which result in altered gene expression.…”

ΔFosB Induction in Prefrontal Cortex by Antipsychotic Drugs is Associated with Negative Behavioral Outcomes

“…DFosB is a member of the Fos family of transcription factors, but is unique in its stable accumulation in the brain in response to a range of chronic stimuli Nestler, 2008). Both first and second generation antipsychotic drugs have been shown to increase DFosB expression in several limbic brain regions including the prefrontal cortex (PFC) (Atkins et al, 1999;Hiroi and Graybiel, 1996;Kontkanen et al, 2002;Perrotti et al, 2005), which is highly implicated in the cognitive deficits associated with schizophrenia.…”

Fluoxetine Epigenetically Alters the CaMKIIα Promoter in Nucleus Accumbens to Regulate ΔFosB Binding and Antidepressant Effects

“…We have identified numerous target genes for DFosB through gene microarray or chromatin immunoprecipitation (ChIP) technology (McClung and Nestler, 2003;Nestler, 2008;Renthal et al, 2009), although study of the role of specific target genes in depression models is just beginning. The neuronally enriched calcium/calmodulin-dependent protein kinase II (CaMKII) was identified originally as a DFosB target in NAc after cocaine exposure using genomewide approaches (McClung and Nestler, 2003), and we have recently verified this finding by showing that DFosB binding to the CaMKIIa gene promoter is both necessary and sufficient for the kinase's induction in NAc by cocaine .…”