Since I've literally just written an essay in this reply, there may be typos that I've missed which make a sentence read somewhat retardedly. I apologize in advance.
I also tried to use precise language to avoid overgeneralizing any of the statements involving what is known about the role of ΔFosB and its transcriptional targets in addiction. If I said something that anyone thinks is stupid/overgeneralized, I'd appreciate it if you'd point it out so that I can clarify my intended meaning or provide a reference.
To the extent that synaptic remodeling can be reversed, reducing levels of deltaFosB may be able to negate some changes that underlie addictive behavior, although there are other factors that also contribute to addiction. For example, withdrawal also plays a role in compulsive drug use and the circuits that drive those adaptations do not completely overlap with the circuits that are involved in habit formation and reinforcement learning.
Dependence/withdrawal isn't strictly associated with an addiction because they're not mediated by the same biomolecular mechanisms, but when addictive stimuli induce both a state of addiction and dependence, it certainly does exacerbate an addiction like you suggest. Some behavioral addictions, the dopamine dysregulation syndrome, and sometimes even drug addictions can occur without clinically significant manifestations of withdrawal symptoms from (physical/psychological) dependence. Dependence to a drug can also occur without an addiction (e.g., benzos cause dependence but not addiction; the same is true with propranolol and clonidine). IMO it's best to think of addiction and dependence as different disorders because their mechanisms differ; hence, a perfectly targeted treatment at the molecular level for an addiction wouldn't be an effective treatment for dependence and vice versa. Physical and psychological dependence are caused by different cellular mechanisms as well, but that's an unrelated point.
What is the purpose of FOSB.
Proteins don't really have a "purpose" per se, but the
function of ΔFosB varies by cell type.
In D1-type medium spiny neurons (MSNs) in the nucleus accumbens (mainly the shell, although the core is involved too), ΔFosB overexpression induces the initial
1 state of addiction by working with epigenetic proteins that function as transcriptional corepressors and coactivators to modify the expression of its transcriptional targets; some of these ΔFosB targets are also transcription factors which in turn affect the expression of other genes. These effects of ΔFosB on gene transcription within the neuron, along with it's stupidly long half-life which allows it to persist in cells for an abnormally+exceptionally long time (the half-life of the 35-37kD ΔFosB isoforms, which are the phosphorylated isoforms of the 33kD variant which is induced by drug exposure, is ~2 orders of magnitude longer than the regular FOS protein) is why it has been called a "master control protein" as a mechanism of addiction: it's a transcription factor that remains in neurons for
far longer than
any other transcription factor which is present in the cell and, for the duration that it persists in the cell, it continues to affect the expression of its transcriptional targets, some of which are transcription factors with their own transcriptional targets. The primary neuropsychological effect of all its transcriptional activity in D1-type NAcc neurons is to amplify incentive salience for positively reinforcing stimuli which are associated with the addictive stimulus (i.e., the addictive drug itself as well as its associated drug cues, like the sight of a crack pipe for a crack cocaine addict); this amplified "incentive salience" is perceived as an overwhelming urge/"wanting" (i.e., craving) for an addictive stimulus, and it's the core driver of drug self-administration from a drug addiction. [This is all stated and referenced in the text, tables, and diagrams in the
ΔFosB and
Addiction#Reward_sensitization sections on Wikipedia; this is basically just a brief summary of what I've written there.]
At much more normal (relatively low) levels of expression, ΔFosB in D1-type NAcc neurons makes an animal more resilient to various forms of chronic "defeat stress", thereby preventing the development of behaviors associated with depression (an example of a depression-related behavior that is associated with defeat stress is
learned helpessness). Animals with higher levels of ΔFosB expression tend to endure these chronic stressors for longer periods before succumbing to them and developing a depression-related behavioral phenotype. Antidepressants like fluoxetine also mildly increase ΔFosB expression in these neurons, and this has been proposed as one of the transcriptional mechanisms in neurons through which antidepressant drugs exert a therapeutic effect on symptoms of major depressive disorder (e.g.,
see this review). For context, the timescale of clinically significant changes in gene expression from the use of antidepressants at therapeutic doses is consistent with the amount of time it takes for antidepressants to alter depressive symptoms.
Increases in ΔFosB expression in
dorsal striatal D1-type MSNs induces locomotor sensitization by inducing NF-κB expression (possibly by other mechanisms as well), and it has been shown to cause dyskinesias when induced via viral vectors in these neurons in lab animals (see
the "Other functions in the brain" section).
What is currently known about the functional role of ΔFosB within the hippocampus in relation to learning is
summarized in this abstract.
ΔFosB expression is known to be induced in other brain structures by addictive drugs, including the prefrontal cortex, amygdala, rostromedial tegmental nucleus (ΔFosB in the RMTg is induced only by psychostimulants, not opiates or other addictive drugs), and elsewhere; the role/function of ΔFosB expression in these other brain structures, and consequently the significance of ΔFosB expression in these structures in relation to addiction, is currently unknown at the moment.
Outside the brain, FosB and ΔFosB are both involved in ostersclerosis in bone cells. As you can probably figure out from FosB's full name, "FBJ murine osteosarcoma viral oncogene homolog B", it's also a gene which is utilized by a retrovirus to cause a form of bone cancer. I don't think the ΔFosB splice variant has any particular significance in relation to FosB's viral oncogenesis though.
I have no clue how ΔFosB affects any other cell types besides what I've covered here.
1 By "initial state", I'm referring to the sensitization of drug reward. An addiction also involves learning processes associated with the development of behavioral responses to addiction-related drug cues (the dorsal striatum and NAcc are critically involved in this process) and the cravings associated with these cues. Essentially, this late phase is where an addict "learns" to associate neutral stimuli with the addictive stimulus, in turn establishing some of these previously neutral and subsequently drug-paired stimuli (i.e., drug cues) as conditioned/secondary positive reinforcers; other, less significant forms of associative learning involved in an addiction include things like the development of a conditioned place preference (CPP), which occurs both in humans as well as lab animals. Healthy individuals can develop CPPs with no risk of developing an addiction in response to addictive drug use though (e.g.,
short-term use of an ADHD stimulant at therapeutic doses induces a CPP in humans), so it's not inherently pathological. All of this associative learning arises from plasticity in a number of brain structures within the reward system that are interconnected with the striatum; all drug cue-induced cravings, which involves conditioned/secondary positive reinforcement where the drug cue is the secondary reinforcer, require the sensitization of incentive salience (i.e., the amplification of wanting/desire/craving), which arises through ΔFosB overexpression in D1-type NAcc MSNs, particularly in the NAcc shell since it's the brain structure that assigns incentive salience to a rewarding stimulus.
However I wonder if its role is more than that, Maybe a neuroprotective roll. Does anyone know if it is linked to Oxidative stress?
There's no known relationship between the two at the moment. If ΔFosB has
any effect on neuronal survival, I imagine that it would probably be almost entirely mediated through one of its transcriptional target:
NF-κB. Oxidative stress could conceivably (but probably doesn't) affect the induction/level of ΔFosB expression.
would blocking delta FOSB reverse part of an addictive behaviour. I know it won't solve the problem, as addiction is more complex than that.
If ΔFosB were suddenly repressed in D1-type NAcc MSNs (i.e., its expression suddenly plummets) without affecting the expression of other genes, it would probably prevent any further development of the addiction phenotype (i.e., "wanting"/craving and drug self-administration would either remain fixed, or possibly even be reduced, instead of slowly increase over time); that's only a guess, since selective ΔFosB repression hasn't been done in an experiment AFAIK. Experiments that have blocked/reversed ΔFosB-mediated effects in neurons (i.e., its transcriptional, synaptic, and behavioral effects) involve the use of
viral vectors (e.g., the adeno-associated virus) to transfer a gene that inhibits ΔFosB induction and opposes its function (e.g., the epigenetic histone methyltransferase enzyme
G9a, the transcription factors
ΔJunD or ΔcJun, and other
more complex genetically engineered epigenetic proteins, as described in this lay-summary) into neurons. Since NAcc G9a expression in D1-type MSNs increases from the chronic use of class I HDAC inhibitors in lab animals, drugs such as butyric acid (butyrate salts) which inhibit the class I HDAC enzymes (HDAC1, HDAC2, HDAC3, HDAC8 )
might be an effective pharmacotherapy for all forms of addiction in humans. [See the 3rd paragraph, including the 2 notes within it, under
ΔFosB#Role in addiction if you care to know more]
