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Review. Transcriptional mechanisms of addiction: role of DeltaFosB - PubMed

Eric J Nestler  1

Review

Review. Transcriptional mechanisms of addiction: role of DeltaFosB

Eric J Nestler. Philos Trans R Soc Lond B Biol Sci. .

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 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.

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Figures

Figure 1

Biochemical basis of ΔFosB's unique stability: (a) FosB (338 aa, Mr approx. 38 kD) and (b) ΔFosB (237 aa, Mr approx. 26 kD) are encoded by the fosB gene. ΔFosB is generated by alternative splicing and lacks the C-terminal 101 amino acids present in FosB. Two mechanisms are known that account for ΔFosB's stability. First, ΔFosB lacks two degron domains present in the C-terminus of full-length FosB (and found in all other Fos family proteins as well). One of these degron domains targets FosB for ubiquitination and degradation in the proteasome. The other degron domain targets FosB degradation by a ubiquitin- and proteasome-independent mechanism. Second, ΔFosB is phosphorylated by casein kinase 2 (CK2) and probably by other protein kinases (?) at its N-terminus, which further stabilizes the protein.

Figure 2

Scheme showing the gradual accumulation of ΔFosB versus the rapid and transient induction of other Fos family proteins in response to drugs of abuse. (a) The autoradiogram illustrates the differential induction of Fos family proteins in the nucleus accumbens by acute stimulation (1–2 hours after a single cocaine exposure) versus chronic stimulation (1 day after repeated cocaine exposure). (b) (i) Several waves of Fos family proteins (comprising c-Fos, FosB, ΔFosB (33 kD isoform), and possibly (?) Fra1, Fra2) are induced in nucleus accumbens and dorsal striatal neurons by acute administration of a drug of abuse. Also induced are biochemically modified isoforms of ΔFosB (35–37 kD); they are induced at low levels by acute drug administration, but persist in brain for long periods due to their stability. (ii) With repeated (e.g. twice daily) drug administration, each acute stimulus induces a low level of the stable ΔFosB isoforms. This is indicated by the lower set of overlapping lines that indicate ΔFosB induced by each acute stimulus. The result is a gradual increase in the total levels of ΔFosB with repeated stimuli during a course of chronic treatment. This is indicated by the increasing stepped line in the graph.

Figure 3

Epigenetic mechanisms of ΔFosB action. The figure illustrates the very different consequences when ΔFosB binds to a gene that it activates (e.g. cdk5) versus represses (e.g. c-fos). (a) At the cdk5 promoter, ΔFosB recruits HAT and SWI–SNF factors, which promote gene activation. There is also evidence for exclusion of HDACs (see text). (b) By contrast, at the c-fos promoter, ΔFosB recruits HDAC1 as well as perhaps HMTs which repress gene expression. A, P and M depict histone acetylation, phosphorylation and methylation, respectively.

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