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. 2012 Dec;10(3):136-43.
doi: 10.9758/cpn.2012.10.3.136. Epub 2012 Dec 20.

Transcriptional Mechanisms of Drug Addiction

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Free PMC article

Transcriptional Mechanisms of Drug Addiction

Eric J Nestler. Clin Psychopharmacol Neurosci. .
Free PMC article

Abstract

Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state. Numerous transcription factors, proteins that bind to regulatory regions of specific genes and thereby control levels of their expression, have been implicated in the addiction process over the past decade or two. Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction. As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype. Current efforts are geared toward understanding the range of target genes through which these transcription factors produce their functional effects and the underlying molecular mechanisms involved. This work promises to reveal fundamentally new insight into the molecular basis of addiction, which will contribute to improved diagnostic tests and therapeutics for addictive disorders.

Keywords: Chromatin remodeling; Epigenetics; Nucleus accumbens; Orbitofrontal cortex; Transcription factors; Ventral tegmental area.

Figures

Fig. 1
Fig. 1
Transcriptional actions of drugs of abuse. Although drugs of abuse act initially on their immediate protein targets at the synapse, their long-term functional effects are mediated in part via regulation of downstream signaling pathways which convertge on the cell nucleus. Here, drug regulation of transfactors leads to the stable regulation of specific target genes and to the lasting behavioral abnormalities that characterize addiction.
Fig. 2
Fig. 2
Distinct temporal properties of drug regulation of ΔFosB vs. CREB. (A) ΔFosB. The top graph shows several waves of Fos family proteins (comprised of c-Fos, FosB, ΔFosB [33 kD isoform], Fra1, Fra2) induced in nucleus accumbens 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. The lower graph shows that 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, which 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. (B) CREB. Activation of CRE transcriptional activity, mediated via phosphorylation and activation of CREB and possibly via the induction of certain ATFs, occurs rapidly and transiently in nucleus accumbens in response to acute drug administration. This "peak and trough" pattern of activation persists through chronic drug exposure, with CRE transcription levels reverting to normal within 1-2 days of drug withdrawal.
Fig. 3
Fig. 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). At the Cdk5 promoter (A), ΔFosB recruits histone acetyltransferases (HAT) and chromatin remodeling proteins (e.g., SWI-SNF factors), which promote gene activation. There is also evidence for exclusion of histone deacetylases (HDAC). In contrast, at the c-Fos promoter (B), ΔFosB recruits HDACs as well as histone methytransferases (HMT), which repress gene expression. A, P, and M depict histone acetylation, phosphorylation, and methylation, respectively.

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