"Substance use disorder" and "addiction" are not interchangeable/synonymous terms, but "severe substance use disorder" and "addiction" are. There is no contradiction in this statement. Read the review for context.
So what then is the useful reason for pointing that out? -- what confuses me is how providing that info helps you to make a point. We are discussing addiction, so if "severe substance use disorder" and addiction are synonymous, then what you should look up is the criteria for severe substance use disorder. That is what I looked up. The entire point of this discussion is what are the criteria for addiction, and those can be found in many articles about addiction, or by consulting the DSM-V and looking up the criteria for "severe substance use disorder". For someone to be diagnosed with severe substance use disorder, one of the criteria is experiencing withdrawal. I'm just not following how pointing out the difference between addiction and low severity SUD (which is what used to be called dependence) really addresses this discussion in a useful way.
[
WRT ΔFosB, none of the 3 studies that you mentioned even hint that exposure to non-addictive stimuli induces ΔFosB overexpression. Those papers only mention the term "overexpression" in the context of viral vector-mediated gene (i.e., ΔFosB) transfer.
That is a completely and utterly inaccurate description of those studies. Maybe the issue here is the use of terminology of "overexpression" vs "increased expression" vs "induced expression" vs. "induction of expression"? Those terms are synonyms. "Overexpression" usually refers to expression increased above baseline level
due to some experimental manipulation, but in this context it means exactly the same thing as increased expression. In other words, a study may say "We altered the promoter for gene X so that the gene was overexpressed in the brain." That is just saying that gene expression increased above baseline levels.
If you don't believe me about this language, take a look at the following passage, which describes the effects of stress and chronic drug administration on ΔFosB in exactly the same terms:
http://www.nature.com/npp/journal/v38/n11/full/npp2013130a.html
"ΔFosB is considered a molecular marker for chronic stimulation of reward circuitry, stress-induced neuroplasticity, and sensitization to psychostimulants.
ΔFosB, barely detectable immediately after acute stimuli, accumulates to considerable levels after repeated social defeat stress or repeated drug administration and persists due to its stability (Nestler et al, 1999; Nikulina et al, 2008; Perrotti et al, 2004)."
Here are several passages from papers showing that stress and other stimuli can markedly increase the expression of ΔFosB in NACC:
https://www.ncbi.nlm.nih.gov/pubmed/24259563
"
The transcription factor, ΔFosB, is robustly and persistently induced in striatum by several chronic stimuli, such as drugs of abuse, antipsychotic drugs, natural rewards, and stress. However, very few studies have examined the degree of ΔFosB induction in the two striatal medium spiny neuron (MSN) subtypes. We make use of fluorescent reporter BAC transgenic mice to evaluate induction of ΔFosB in dopamine receptor 1 (D1) enriched and dopamine receptor 2 (D2) enriched MSNs in ventral striatum, nucleus accumbens (NAc) shell and core, and in dorsal striatum (dStr) after chronic exposure to several drugs of abuse including cocaine, ethanol, Δ(9)-tetrahydrocannabinol, and opiates; the antipsychotic drug, haloperidol; juvenile enrichment; sucrose drinking; calorie restriction; the serotonin selective reuptake inhibitor antidepressant, fluoxetine; and social defeat stress.
Our findings demonstrate that chronic exposure to many stimuli induces ΔFosB in an MSN-subtype selective pattern across all three striatal regions. To explore the circuit-mediated induction of ΔFosB in striatum, we use optogenetics to enhance activity in limbic brain regions that send synaptic inputs to NAc; these regions include the ventral tegmental area and several glutamatergic afferent regions: medial prefrontal cortex, amygdala, and ventral hippocampus. These optogenetic conditions lead to highly distinct patterns of ΔFosB induction in MSN subtypes in NAc core and shell. Together, these findings establish selective patterns of ΔFosB induction in striatal MSN subtypes in response to chronic stimuli and provide novel insight into the circuit-level mechanisms of ΔFosB induction in striatum."
Here is a quote from another paper:
"This time-dependent pattern of induction of Fos family proteins in the frontal cortex by acute versus chronic stress is highly similar to that seen in response to other treatments, e.g., chronic electroconvulsive seizures in the frontal cortex (Hope et al., 1994a),
or chronic administration of a drug of abuse (Hope et al., 1994b; Moratalla et al., 1996) or
antipsychotic drugs (Doucet et al., 1996; Hiroi and Graybiel, 1996; Atkins et al., 1999) in the striatum. In each of these studies, the identification of the 35-37 kDa band as modified isoforms of ΔFosB and the 33 kDa protein as the native form of the protein is based on the following lines of evidence: (1) overexpression of ΔFosB cDNA in cultured cells initially produces the 33 kDa band, which is gradually replaced by the 35-37 kDa band during more prolonged expression (Chen et al., 1997; Alibhai et al., 2004); (2) the 33 kDa and 35-37 kDa bands are both recognized by anti-FosB(N-terminus) antibody and not by anti-FosB(C-terminus) antibody (Hope et al., 1994b; Chen et al., 1995, 1997); and (3) both the 33 and 35-37 kDa bands are lost in fosB knock-out mice (Hiroi et al., 1997, 1998; Mandelzys et al., 1997). The nature of the modifications that convert the 33 kDa band to the 35-37 kDa band has remained unknown, but recent evidence suggests that phosphorylation of the protein is involved (Ulery and Nestler, 2004).
The effects of acute and chronic stress on levels of Fos family proteins in the frontal cortex were mirrored in certain other brain regions. The most dramatic of these regions was the NAc, where induction of c-Fos, FosB, and Fra-1/2 after acute stress, their desensitization after chronic stress, and the unique induction of the 35-37 kDa isoforms of ΔFosB after chronic stress were as prominent as those seen in the frontal cortex (Fig. 1C). Qualitatively similar results were obtained for the lateral septum, dorsal striatum, amygdala, and locus ceruleus, although the magnitude of induction of the various proteins after acute and chronic stress was generally not as large as that seen in the frontal cortex and NAc (data not shown). In contrast, no induction of ΔFosB (or any other Fos family protein) was apparent after chronic stress in other regions analyzed, which included the hippocampus, parietal cortex, and ventral tegmental area (data not shown).
We next analyzed the time course by which repeated restraint stress caused the induction of the 35-37 kDa ΔFosB isoforms. As mentioned earlier, no induction was seen 24 hr after a single period of restraint, but the effect became near-maximal after 5 d of daily restraint stress. No additional induction was seen after 10 d of daily restraint stress. This was true in all regions analyzed, e.g., in the frontal cortex, NAc, lateral septum, and dorsal striatum (Fig. 1D). Moreover, in each of these regions, levels of the ΔFosB isoforms remained significantly elevated 1 week after the last stress treatment, consistent with the highly stable nature of these isoforms (Fig. 1E).
A different form of chronic stress, chronic unpredictable stress, also led to the accumulation of the 35-37 kDa isoforms of ΔFosB in the same brain regions affected by chronic restraint stress. In fact, the magnitude of ΔFosB induction tended to be greater with chronic unpredictable stress (Fig. 1F), perhaps because rats show less habituation to this form of stress (where the individual stresses vary from day to day) compared with restraint stress (Ortiz et al., 1996)."
Here is the abstract of another paper:
https://www.ncbi.nlm.nih.gov/pubmed/15564575
"Acute and chronic stress differentially regulate immediate-early gene (IEG) expression in the brain. Although acute stress induces c-Fos and FosB, repeated exposure to stress desensitizes the c-Fos response, but FosB-like immunoreactivity remains high. Several other treatments differentially regulate IEG expression in a similar manner after acute versus chronic exposure. The form of FosB that persists after these chronic treatments has been identified as DeltaFosB, a splice variant of the fosB gene. This study was designed to determine whether the FosB form induced after chronic stress is also DeltaFosB and to map the brain regions and identify the cell populations that exhibit this effect. Western blotting, using an antibody that recognizes all Fos family members, revealed that acute restraint stress caused robust induction of c-Fos and full-length FosB, as well as a small induction of DeltaFosB, in the frontal cortex (fCTX) and nucleus accumbens (NAc). The induction of c-Fos (and to some extent full-length FosB) was desensitized after 10 d of restraint stress, at which point levels of DeltaFosB were high. A similar pattern was observed after chronic unpredictable stress.
By use of immunohistochemistry, we found that chronic restraint stress induced DeltaFosB expression predominantly in the fCTX, NAc, and basolateral amygdala, with lower levels of induction seen elsewhere. These findings establish that chronic stress induces DeltaFosB in several discrete regions of the brain. Such induction could contribute to the long-term effects of stress"
[A fairly good, but not fully comprehensive, review on the role of ΔFosB in addiction is PMID 25083822. I'd suggest that you read the entire review to gain a foundational understanding on the significance of that transcription factor in addiction, since you seem to be off-handedly discounting it.
Also,
"This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure." This is part of what I was referring to in my previous post. This "
necessary and sufficient" clause is a logical equivalence, meaning that ΔFosB overexpression that occurs by means of any mechanism induces addictive plasticity AND such plasticity never occurs without it.
I have certainly read the reviews. You are misunderstanding what they mean in that quote. Addiction is dependent on plasticity in accumbens, and so long-lasting changes in plasticity following ΔFosB expression increases are going to play an important role in the remodelling of striatal citcuits in addiction. But that doesn't mean that the only type of accumbens plasticity (and increase of ΔFosB expression) occurs in addiction. There are plenty of other situations, such as chronic stress, that cause significant plasticity in accumbens. And in those situations, the above quote might also be valid (eg, it might be equally valid to write that the ΔFosB expression change in accumbens might be necessary and sufficient for many changes in the brain brought by chronic stress exposure).
If what you were claiming is true, then studies need to not only show that ΔFosB expression increases are necessary and sufficient for compulsive drug use, but also to show that such changes are EXCLUSIVE to compulsive drug use. And that last criteria is something that is not actually true. The striatum, including NACC, is involved in the development of habitual behavioral patterns, so any time there a behavior becomes habitual there is going to be striatal plasticity and increased expression of ΔFosB.
