FOSB

FBJ murine osteosarcoma viral oncogene homolog B, also known as FOSB or FosB, is a is_associated_with::protein that, in humans, is encoded by the FOSB is_associated_with::gene.

The FOS gene family consists of 4 members: FOS, FOSB, is_associated_with::FOSL1, and is_associated_with::FOSL2. These genes encode is_associated_with::leucine zipper proteins that can is_associated_with::dimerize with proteins of the JUN family (e.g., is_associated_with::c-Jun, is_associated_with::JunD), thereby forming the is_associated_with::transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. FosB and its truncated splice variants ΔFosB and (further truncated) Δ2ΔFosB are all involved in is_associated_with::osteosclerosis, even though Δ2ΔFosB lacks a known transactivation domain, preventing it from affecting gene transcription through the AP-1 complex.

The ΔFosB splice variant has been identified as playing a central, crucial (is_associated_with::necessary and sufficient) role in the development and maintenance of pathological behavior and is_associated_with::neural plasticity involved in both is_associated_with::behavioral addictions (associated with is_associated_with::natural rewards) and is_associated_with::drug addictions. E.g., ΔFosB overexpression causes the development addiction-related structural neuroplasticity to occur throughout the is_associated_with::reward system. ΔFosB differs from the full length FosB and further truncated Δ2ΔFosB in its capacity to produce these effects, as only is_associated_with::accumbal ΔFosB overexpression is associated with pathological responses to drugs.

ΔFosB
ΔFosB or Delta FosB is a truncated is_associated_with::splice variant of FosB. ΔFosB has been implicated as a critical factor in the development of virtually all forms of behavioral and is_associated_with::drug addictions. In the brain's is_associated_with::reward system, it is linked to changes in a number of other gene products, such as is_associated_with::CREB and is_associated_with::sirtuins. In the body, ΔFosB regulates the commitment of mesenchymal is_associated_with::precursor cells to the is_associated_with::adipocyte or is_associated_with::osteoblast lineage.

In the is_associated_with::nucleus accumbens, ΔFosB functions as a "sustained molecular switch" and "master control protein" in the development of an is_associated_with::addiction. In other words, once "turned on" (sufficiently overexpressed) ΔFosB triggers a series of transcription events that ultimately produce an addictive state (i.e., compulsive reward-seeking involving a particular stimulus); this state is sustained for months after cessation of drug use due to the abnormal and exceptionally long is_associated_with::half-life of ΔFosB isoforms. ΔFosB expression in is_associated_with::D1-type nucleus accumbens is_associated_with::medium spiny neurons directly and positively regulates drug is_associated_with::self-administration and reward is_associated_with::sensitization through is_associated_with::positive reinforcement while decreasing sensitivity to aversion. Based upon the accumulated evidence, a medical review from late 2014 argued that is_associated_with::accumbal ΔFosB expression can be used as an addiction biomarker and that the degree of accumbal ΔFosB induction by a drug is a metric for how addictive it is relative to others.

Role in addiction
Addiction from chronic is_associated_with::addictive drug use involves alterations in is_associated_with::gene expression in the is_associated_with::mesocorticolimbic projection, which arise through is_associated_with::transcriptional and is_associated_with::epigenetic mechanisms. The most important is_associated_with::transcription factors that produce these alterations are ΔFosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NF-κB). ΔFosB is the most significant biomolecular mechanism in addiction since its viral or genetic overexpression (through chronic addictive drug use) in is_associated_with::D1-type is_associated_with::medium spiny neurons in the is_associated_with::nucleus accumbens is is_associated_with::necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in is_associated_with::self-administration and reward is_associated_with::sensitization) seen in drug addiction; it has been implicated in addictions to alcohol (ethanol), is_associated_with::cannabinoids, is_associated_with::cocaine, is_associated_with::methylphenidate, is_associated_with::nicotine, is_associated_with::opioids, is_associated_with::phencyclidine, is_associated_with::propofol, and is_associated_with::substituted amphetamines, among others. is_associated_with::ΔJunD, a transcription factor, and G9a, a is_associated_with::histone methyltransferase, both directly oppose the induction of ΔFosB (i.e., increases in its expression). Increases in nucleus accumbens ΔJunD expression using is_associated_with::viral vectors (a genetically engineered virus) can reduce or, with a large increase, even block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).

ΔFosB also plays an important role in regulating behavioral responses to natural (non-drug) rewards, such as palatable food, sex, and exercise. Natural rewards, like drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression. Consequently, ΔFosB is the key mechanism involved in addictions to natural rewards (i.e., behavioral addictions) as well; in particular, ΔFosB in the nucleus accumbens is critical for the is_associated_with::reinforcing effects of sexual reward. Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., is_associated_with::amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional cross-is_associated_with::sensitization effects that are mediated through ΔFosB. This phenomenon is notable since, in humans, a is_associated_with::dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking is_associated_with::dopaminergic medications.

ΔFosB inhibitors (drugs or treatments that oppose its action or reduce its expression) may be an effective treatment for addiction and addictive disorders.

Plasticity in cocaine addiction
ΔFosB levels have been found to increase upon the use of cocaine. Each subsequent dose of cocaine continues to increase ΔFosB levels with no ceiling of tolerance. Elevated levels of ΔFosB leads to increases in brain-derived neurotrophic factor (is_associated_with::BDNF) levels, which in turn increases the number of dendritic branches and spines present on neurons involved with the nucleus accumbens and is_associated_with::prefrontal cortex areas of the brain. This change can be identified rather quickly, and may be sustained weeks after the last dose of the drug.

Transgenic mice exhibiting inducible expression of ΔFosB primarily in the nucleus accumbens and is_associated_with::dorsal striatum exhibit sensitized behavioural responses to cocaine. They self-administer cocaine at lower doses than control, but have a greater likelihood of is_associated_with::relapse when the drug is withheld. ΔFosB increases the expression of is_associated_with::AMPA receptor subunit GluR2 and also decreases expression of is_associated_with::dynorphin, thereby enhancing sensitivity to reward.

Other functions in the brain
ΔFosB overexpression in the is_associated_with::dorsal striatum (is_associated_with::nigrostriatal dopamine pathway) via is_associated_with::viral vectors induces is_associated_with::levodopa-induced dyskinesias in animal models of is_associated_with::Parkinson's disease. Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias; postmordem studies of individuals with Parkinson's disease that were treated with is_associated_with::levodopa have also observed similar dorsal striatal ΔFosB overexpression. is_associated_with::Levetiracetam, an is_associated_with::antiepileptic drug which has been demonstrated to reduce the severity of levodopa-induced dyskinesias, has been shown to dose-dependently decrease the induction of dorsal striatal ΔFosB expression in rats when co-administered with levodopa; the is_associated_with::signal transduction involved in this effect is unknown.

ΔFosB expression in the is_associated_with::nucleus accumbens shell increases resilience to stress and is induced in this region by acute exposure to is_associated_with::social defeat stress.