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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 striatum 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. (This definition may be outdated - see the DesignNote.)
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