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Pathways FOSB gene expression and drug abuse
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Submitted by:  Michael Shih, PhDEmail Michael Shih, PhD Guru: Email

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Description: Description: Drug addiction is associated with long-term behavioral changes, suggesting a long-lived transcriptional regulator that responds to chronic drug exposure might cause long-term changes in neuronal function. Neurons in the nucleus accumbens and striatium are involved in addiction and have altered synaptic properties in response to chronic drug exposure. Along with JunD, delta-FosB is a component of an AP-1 transcription factor that accumulates in these key brain regions after chronic exposure to drugs of abuse, including morphine, amphetamine, alcohol, and cocaine. Delta-FosB is an unusually stable splice variant of the immediate early FosB gene, accumulating and persisting in the brain long after drug is removed. One component of FosB stability is post-translational modification through phosphorylation. Genetically modified mice that selectively overexpress this protein in neurons have increased sensitivity to cocaine and increased apparent reward response to drug administration, as expected in addiction, supporting the role of delta-FosB in addiction. The target genes regulated by delta-FosB include the GluR2 subunit of the AMPA glutamate receptor. Increased expression of GluR2 modifies the conductance and calcium flux of neurons, and may be responsible for increased reward responses to drug. Another target of delta-FosB is the dynorphin gene, the ligand for the kappa opioid receptor, further altering reward responses to drugs. The cell cycle checkpoint kinase cdk2 is activated by delta-FosB and acts on Darpp-32 to alter dopaminergic signaling. Although delta-FosB is very stable, it does degrade after several weeks, while the behavioral changes of drug addiction persist much longer after drug exposure ends. Changes in chromatin structure or changes in synaptic structure induced initially by delta-FosB may persist long after delta-FosB is no longer present, allowing behavioral changes to persist.
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references: references: Hiroi, N. et al. (1997) FosB mutant mice: loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaines psychomotor and rewarding effects. Proc Natl Acad Sci U S A 94(19), 10397-402

Kelz, M.B. et al. (1999) Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine. Nature 401(6750), 272-6

Nestler, E.J., Barrot, M., Self, D.W. (2001) DeltaFosB: a sustained molecular switch for addiction. Proc. Natl. Acad. Sci. U S A 98(20), 11042-6

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