FOSB

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

The FOS gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family (e.g., c-Jun, JunD), thereby forming the 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 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 (necessary and sufficient) role in the development and maintenance of pathological behavior and neural plasticity involved in both behavioral addictions (associated with natural rewards) and drug addictions. For example, ΔFosB overexpression triggers the development of addiction-related structural neuroplasticity throughout the reward system. ΔFosB differs from the full length FosB and further truncated Δ2ΔFosB in its capacity to produce these effects, as only accumbal ΔFosB overexpression is associated with pathological responses to drugs.

ΔFosB

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

In the nucleus accumbens, ΔFosB functions as a "sustained molecular switch" and "master control protein" in the development of an 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 half-life of ΔFosB isoforms. ΔFosB expression in D1-type nucleus accumbens medium spiny neurons directly and positively regulates drug self-administration and reward sensitization through positive reinforcement while decreasing sensitivity to aversion. Based upon the accumulated evidence, a medical review from late 2014 argued that 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 and dependence glossary
• addiction – a state characterized by compulsive engagement in rewarding stimuli despite adverse consequences
• addictive behavior – a behavior that is both rewarding and reinforcing
• addictive drug – a drug that is both rewarding and reinforcing
• dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
• drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
• drug withdrawal – symptoms that occur upon cessation of repeated drug use
• physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
• psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
• reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
• rewarding stimuli – stimuli that the brain interprets as intrinsically positive or as something to be approached
• sensitization – an amplified response to a stimulus resulting from repeated exposure to it
• tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction

Note: colored text contains article links.

Nuclear pore

Nuclear membrane

Plasma membrane

Ca_v1.2

NMDAR

AMPAR

DRD1

DRD5

DRD2

DRD3

DRD4

G_s

G_i/o

cAMP

cAMP

PKA

CaM

CaMKII

DARPP-32

PP1

PP2B

CREB

ΔFosB

JunD

c-Fos

SIRT1

HDAC1

This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants, postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation. Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors; c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron. A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated high-dose exposure to stimulants through this process. ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.

Addiction from chronic addictive drug use involves alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms. The most important 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 D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and behavioral effects (e.g., expression-dependent increases in self-administration and reward sensitization) seen in drug addiction; it has been implicated in addictions to alcohol (ethanol), cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others. ΔJunD, a transcription factor, and G9a, a histone methyltransferase, both oppose the function and induction of ΔFosB (i.e., increases in its expression). Increases in nucleus accumbens ΔJunD expression using viral vectors can also 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 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 reinforcing effects of sexual reward. Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional reward cross-sensitization effects that are mediated through ΔFosB. This phenomenon is notable since, in humans, a 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 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. Current medical reviews of research involving lab animals have identified a drug class – class I histone deacetylase inhibitors – that indirectly inhibits the function and further increases in the expression of accumbal ΔFosB by inducing G9a expression in the nucleus accumbens after prolonged use. These reviews and subsequent preliminary evidence which used oral administration or intraperitoneal administration of the sodium salt of butyric acid or other class I HDAC inhibitors for an extended period indicate that these drugs have efficacy in reducing addictive behavior in lab animals that have developed addictions to ethanol, psychostimulants (i.e., amphetamine and cocaine), nicotine, and opiates; however, as of August 2015 no clinical trials involving human addicts and any HDAC class I inhibitors have been conducted to test for treatment efficacy in humans or identify an optimal dosing regimen.

Plasticity in cocaine addiction

See also: Epigenetics of 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 (BDNF) levels, which in turn increases the number of dendritic branches and spines present on neurons involved with the nucleus accumbens and 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 dorsal striatum exhibit sensitized behavioural responses to cocaine. They self-administer cocaine at lower doses than control, but have a greater likelihood of relapse when the drug is withheld. ΔFosB increases the expression of AMPA receptor subunit GluR2 and also decreases expression of dynorphin, thereby enhancing sensitivity to reward.

Top: this depicts the acute expression of various Fos family proteins following an initial exposure to an addictive drug.
Bottom: this illustrates increasing ΔFosB expression from repeated twice daily drug binges, where these phosphorylated (35–37 kD) ΔFosB isoforms persist in mesolimbic dopamine neurons for up to 2 months.

Neural and behavioral effects of validated ΔFosB transcriptional targets

Target gene	Target expression	Neural effects	Behavioral effects
c-Fos	↓	Molecular switch enabling the chronic induction of ΔFosB	–
dynorphin	↓	• Downregulation of κ-opioid feedback loop	• Increased drug reward
NF-κB	↑	• Expansion of Nacc dendritic processes  • NF-κB inflammatory response in the NAcc  • NF-κB inflammatory response in the CP	• Increased drug reward  • Increased drug reward  • Locomotor sensitization
GluR2	↑	• Decreased sensitivity to glutamate	• Increased drug reward
Cdk5	↑	• GluR1 synaptic protein phosphorylation  • Expansion of NAcc dendritic processes	• Decreased drug reward (net effect)

Summary of addiction-related plasticity

Form of neural or behavioral plasticity	Type of reinforcer						Sources
	Opiates	Psychostimulants	High fat or sugar food	Sexual intercourse	Physical exercise (aerobic)	Environmental enrichment
ΔFosB expression in nucleus accumbens D1-type MSNs	↑	↑	↑	↑	↑	↑
Behavioral plasticity
Escalation of intake	Yes	Yes	Yes
Psychostimulant cross-sensitization	Yes	Not applicable	Yes	Yes	Attenuated	Attenuated
Psychostimulant self-administration	↑	↑	↓		↓	↓
Psychostimulant conditioned place preference	↑	↑	↓	↑	↓	↑
Reinstatement of drug-seeking behavior	↑	↑			↓	↓
Neurochemical plasticity
CREB phosphorylation in the nucleus accumbens	↓	↓	↓		↓	↓
Sensitized dopamine response in the nucleus accumbens	No	Yes	No	Yes
Altered striatal dopamine signaling	↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3		↑DRD2	↑DRD2
Altered striatal opioid signaling	↑μ-opioid receptors	↑μ-opioid receptors ↑κ-opioid receptors	↑μ-opioid receptors	↑μ-opioid receptors	No change	No change
Changes in striatal opioid peptides	↑dynorphin	↑dynorphin	↓enkephalin		↑dynorphin	↑dynorphin
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens	↓	↑		↑
Dendritic spine density in the nucleus accumbens	↓	↑		↑

Other functions in the brain

Viral overexpression of ΔFosB in the output neurons of the nigrostriatal dopamine pathway (i.e., the medium spiny neurons in the dorsal striatum) induces levodopa-induced dyskinesias in animal models of Parkinson's disease. Dorsal striatal ΔFosB is overexpressed in rodents and primates with dyskinesias; postmortem studies of individuals with Parkinson's disease that were treated with levodopa have also observed similar dorsal striatal ΔFosB overexpression. Levetiracetam, an 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 signal transduction involved in this effect is unknown.

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

See also

• AP-1 (transcription factor)

Notes

Image legend

External links

• ROLE OF ΔFOSB IN THE NUCLEUS ACCUMBENS
• KEGG Pathway – human alcohol addiction
• KEGG Pathway – human amphetamine addiction
• KEGG Pathway – human cocaine addiction
• FOSB protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.