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Transcriptional mechanisms of drug addiction.

Nestler EJ - Clin Psychopharmacol Neurosci (2012)

Bottom Line: Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state.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.

View Article: PubMed Central - PubMed

Affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, USA.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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Figure 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.

Mentions: ΔFosB is encoded by the FosB gene and shares homology with other Fos family transcription factors, which include c-Fos, FosB, Fra1, and Fra2.5) These Fos family proteins heterodimerize with Jun family proteins (c-Jun, JunB, or JunD) to form active activator protein-1 (AP1) transcription factors that bind to AP1 sites present in the promoters of certain genes to regulate their transcription. These Fos family proteins are induced rapidly and transiently in specific brain regions after acute administration of many drugs of abuse (Fig. 2).2) These responses are seen most prominently in nucleus accumbens and dorsal striatum, but also seen in several other brain areas.6) All of these Fos family proteins, however, are highly unstable and return to basal levels within hours of drug administration.


Transcriptional mechanisms of drug addiction.

Nestler EJ - Clin Psychopharmacol Neurosci (2012)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 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.
Mentions: ΔFosB is encoded by the FosB gene and shares homology with other Fos family transcription factors, which include c-Fos, FosB, Fra1, and Fra2.5) These Fos family proteins heterodimerize with Jun family proteins (c-Jun, JunB, or JunD) to form active activator protein-1 (AP1) transcription factors that bind to AP1 sites present in the promoters of certain genes to regulate their transcription. These Fos family proteins are induced rapidly and transiently in specific brain regions after acute administration of many drugs of abuse (Fig. 2).2) These responses are seen most prominently in nucleus accumbens and dorsal striatum, but also seen in several other brain areas.6) All of these Fos family proteins, however, are highly unstable and return to basal levels within hours of drug administration.

Bottom Line: Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state.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.

View Article: PubMed Central - PubMed

Affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, USA.

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.

No MeSH data available.


Related in: MedlinePlus