Do anti-psychotics affect gene expression like DeltaFosB?

[Cotcha Yankinov]

My textbook says that because sometimes it takes a while for people to respond to anti-psychotics there might be something else going on besides i.e. D2 antagonism - maybe something happening at the gene expression level. Any idea what this might be?

Might strong enough dopamine antagonism allow built-up DeltaFosB to wither away?

 

[dopamimetic]

Hmm, don't think DeltaFosB is primarily involved in the antipsychotic response probably, but interesting question.

Afaik a suggested mechanism for tardive dyskinesia is permanent alteration / over-sensibility of certain dopamine circuits (so that the dyskinesia, once there, worsens when getting off the antagonist) - could this mean that a really careful antagonist cycle might reverse stimulant (ab)use induced anhedonia, fatigue etc or even help with non-stimulant issues like some ADHD symptoms (at the cost of going through some worse weeks of course, but if the effects last for months or longer, this would be worth it- even better when possible to do at night..but well, akathisia is hell)?

You know I dislike dopamine antagonism, but sometimes a potent tool needs indeed just to be used very, very carefully ...

 

[Neuroprotection]

Hmm, don't think DeltaFosB is primarily involved in the antipsychotic response probably, but interesting question.

Afaik a suggested mechanism for tardive dyskinesia is permanent alteration / over-sensibility of certain dopamine circuits (so that the dyskinesia, once there, worsens when getting off the antagonist) - could this mean that a really careful antagonist cycle might reverse stimulant (ab)use induced anhedonia, fatigue etc or even help with non-stimulant issues like some ADHD symptoms (at the cost of going through some worse weeks of course, but if the effects last for months or longer, this would be worth it- even better when possible to do at night..but well, akathisia is hell)?
I would say currently available dopamine antagonists are too unselective and would not rearly enhance reward sensitivity as one would expect.
You know I dislike dopamine antagonism, but sometimes a potent tool needs indeed just to be used very, very carefully ...

May be its possible, if in the future a dopamine antagonist selective to the reward system is developed. For now its probably best to stick to antioxidents and other neuromodulaters that are neuroprotective.

 

[Neuroprotection]

My textbook says that because sometimes it takes a while for people to respond to anti-psychotics there might be something else going on besides i.e. D2 antagonism - maybe something happening at the gene expression level. Any idea what this might be?

Might strong enough dopamine antagonism allow built-up DeltaFosB to wither away?

Sorry I am not sure about that, but I have a question my self. What is the role of delta-fosB in neurons. Does it play a neuroprotective role? Is over expression of this protein neurotoxic, protective or not relevant

 

[serotonin2A]

Sorry I am not sure about that, but I have a question my self. What is the role of delta-fosB in neurons. Does it play a neuroprotective role? Is over expression of this protein neurotoxic, protective or not relevant

DeltaFOSB is a transcription factor, meaning that it regulates gene expression. Genes are stored as DNA sequences, and can be converted to mRNA sequences (transcription), which are used to make proteins (translation). The process of transcription is regulated by numerous proteins, as well as by other DNA sequences.

The mechanism for antipsychotic effects is probably changes in the expression of large numbers of genes -- it doesn't appear that a single protein is responsible.

 

[Cotcha Yankinov]

DeltaFOSB is a transcription factor, meaning that it regulates gene expression. Genes are stored as DNA sequences, and can be converted to mRNA sequences (transcription), which are used to make proteins (translation). The process of transcription is regulated by numerous proteins, as well as by other DNA sequences.

The mechanism for antipsychotic effects is probably changes in the expression of large numbers of genes -- it doesn't appear that a single protein is responsible.

Thank you.

Typically I hear about DeltaFOSB when referring to addiction "sensitization" and such - does it play a role in all dopamine neurons (and therefore normal cognition) or is it mostly important regarding the nucleus accumbens?

 

[PINKoPANaTHER]

Transcription factors like the Fos family control a number of genes, particularly controlling the development of the CNS. It is likely that the DeltaFOSB isoform has downstream effects at many genes, and the changes seen in addiction are part of a complex regulatory imbalance with many other factors, receptors, and second messengers implicated in the process.

As such, the genetic changes from antagonism versus agonism are likely inverse, complex and different. The more you learn about biochemistry, cell/molecular biology, the more it becomes apparent that despite a prevailing mechanistic explanation being available, the vast complexity of interactions in a single cell likely means that there is a lot going on in the background that takes time to uncover. For instance, look up shRNA RNAi and miRNA regulatory systems. These are post-transcriptional regulatory elements that have different mechanisms at different genes, and even mRNA decoys transcribed to distract the miRNAs which can be found in the introns of DNA sequences (pTENB has a duplicate gene with no translatable element, but identical 3' and 5' untranslated regions that often are responsible for txn regulation (most important in this situation is the 3' UTR) where the miRNA targets can bind to, rather than the actual pTENB locus, decreasing its regulatory efficiency - and that gene itself has a complex transcriptional regulatory system and so on. We are only a few pages into the book that is gene regulation (which is thousands of pages long in my estimation).

The point is, that long-term use of any chemical that alters messengers/second messengers, small molecules, or receptor dynamics among other things, is going to accumulate downstream effects at more and more fundamental levels until the effects become semi-permanent or spread to different systems. My graduate work was done on chromatin dynamics, histone regulation, and all forms of molecular regulation of cell function (at the genetic level primarily) and just like I think socrates (?) said, the more you learn, the more you truly see how little you know.

 

[serotonin2A]

does it play a role in all dopamine neurons (and therefore normal cognition) or is it mostly important regarding the nucleus accumbens?

Just to clarify -- the neurons in nucleus accumbens that express DeltaFosB are not dopaminergic. Nucleus accumbens is innervated by axons that release dopamine, but does not contain dopaminergic cell bodies.

 

[Dresden]

DeltaFOSB is a transcription factor, meaning that it regulates gene expression. Genes are stored as DNA sequences, and can be converted to mRNA sequences (transcription), which are used to make proteins (translation). The process of transcription is regulated by numerous proteins, as well as by other DNA sequences.

The mechanism for antipsychotic effects is probably changes in the expression of large numbers of genes -- it doesn't appear that a single protein is responsible.

When a drug alters gene expression, obviously the effects if any are going to be different in each gene and with each drug, but what exactly do the genes do differently after their "expression" is altered by the administration of a drug molecule? I know a gene only codes for the biosynthesis of a particular protein, such as those that make up our bodily morphology, so when a gene's expression is altered that means it produces more or less or no proteins than it would have had it been untouched by by the drug's effect?

 

[Dresden]

Transcription factors like the Fos family control a number of genes, particularly controlling the development of the CNS. It is likely that the DeltaFOSB isoform has downstream effects at many genes, and the changes seen in addiction are part of a complex regulatory imbalance with many other factors, receptors, and second messengers implicated in the process.

As such, the genetic changes from antagonism versus agonism are likely inverse, complex and different. The more you learn about biochemistry, cell/molecular biology, the more it becomes apparent that despite a prevailing mechanistic explanation being available, the vast complexity of interactions in a single cell likely means that there is a lot going on in the background that takes time to uncover. For instance, look up shRNA RNAi and miRNA regulatory systems. These are post-transcriptional regulatory elements that have different mechanisms at different genes, and even mRNA decoys transcribed to distract the miRNAs which can be found in the introns of DNA sequences (pTENB has a duplicate gene with no translatable element, but identical 3' and 5' untranslated regions that often are responsible for txn regulation (most important in this situation is the 3' UTR) where the miRNA targets can bind to, rather than the actual pTENB locus, decreasing its regulatory efficiency - and that gene itself has a complex transcriptional regulatory system and so on. We are only a few pages into the book that is gene regulation (which is thousands of pages long in my estimation).

The point is, that long-term use of any chemical that alters messengers/second messengers, small molecules, or receptor dynamics among other things, is going to accumulate downstream effects at more and more fundamental levels until the effects become semi-permanent or spread to different systems. My graduate work was done on chromatin dynamics, histone regulation, and all forms of molecular regulation of cell function (at the genetic level primarily) and just like I think socrates (?) said, the more you learn, the more you truly see how little you know.

Oh Gosh, you are way beyond me. I was happy enough with my "B" in undergrad biochem.

 

[Cotcha Yankinov]

Just to clarify -- the neurons in nucleus accumbens that express DeltaFosB are not dopaminergic. Nucleus accumbens is innervated by axons that release dopamine, but does not contain dopaminergic cell bodies.

Interesting... Do you think DeltaFOSB is widespread and important for other more normal functions like cognition or neuronal survival/differentiation outside of the realm of addiction? Are there DeltaFOSB knockout studies?

I'm asking these questions in the context of wondering what long term anti-psychotics are doing to my still young brain.

 

[serotonin2A]

http://www.ncbi.nlm.nih.gov/pubmed/8668344

 

[Cotcha Yankinov]

Thank you.

http://www.ncbi.nlm.nih.gov/pubmed/10448191 - " novel isoforms of DeltaFosB accumulate in a region-specific manner in brain uniquely in response to many types of chronic perturbations, including repeated administration of drugs of abuse or of antidepressant or antipsychotic treatments. Importantly, once induced, these DeltaFosB isoforms persist in brain for relatively long periods due to their extraordinary stability. Mice lacking the fosB gene show abnormal biochemical and behavioral responses to chronic administration of drugs of abuse or antidepressant treatments, consistent with an important role for DeltaFosB in mediating long-term adaptations in the brain."

I could understand how SSRI's might cause accumulation of DeltaFOSB but shouldn't anti-psychotics do the opposite? I mean, I thought accumulation of DeltaFOSB (without drugs involved) led to a state that was similar to drug sensitization probably with increased locomotor activity and such, this isn't really something we want to happen with anti-psychotics or schizophrenics who might already have too much dopamine is it? Does this mean that anti-psychotics might have a relatively small effect on DeltaFOSB?

How the heck do dopaminergics cause DeltaFosB accumulation and then dopamine antagonists cause DeltaFosB accumulation?

Excuse me if I'm stuck in this rut of thinking about DeltaFOSB in relation to drug sensitization.

 

[serotonin2A]

Two points:

Schizophrenics don't have "too much dopamine". Blocking D2 is a useful strategy for treating schizophrenia but that isn't because the disease is associated with elevated DA levels.

The fact that FosB is involved in neuronal plasticity explains why both DA agonists and antagonists can potentially cause FosB accumulation -- chronic treatment with either class induces long-term adaptations.

 

[Cotcha Yankinov]

Two points:
Schizophrenics don't have "too much dopamine". Blocking D2 is a useful strategy for treating schizophrenia but that isn't because the disease is associated with elevated DA levels..

I thought some schizophrenics had increased dopamine metabolites - is this a consequence of something else and is hence not the real root of the problem, or is it that just a subset of patients have increased dopamine/dopamine receptors?

The fact that FosB is involved in neuronal plasticity explains why both DA agonists and antagonists can potentially cause FosB accumulation -- chronic treatment with either class induces long-term adaptations.

Are you saying increased DeltaFosB might be a compensation for decreased dopamine? I guess I'm stuck on how an antagonist and agonist can effect the same change because I'm used to thinking about G-proteins causing the cellular change, but because an antagonist can induce DeltaFosB it must not be connected to G-proteins? But then how the heck do dopaminergics induce DeltaFosB?

The only silly explanation I can think of as to why dopamine agonists and antagonists lead to DeltaFosB accumulation is that maybe there is stabilization of DeltaFosB after dopamine receptor down regulation, and that it is essentially the period of dopamine hypo-activity that leads to accumulation of DeltaFosB.

 

[Cotcha Yankinov]

Transcription factors like the Fos family control a number of genes, particularly controlling the development of the CNS. It is likely that the DeltaFOSB isoform has downstream effects at many genes, and the changes seen in addiction are part of a complex regulatory imbalance with many other factors, receptors, and second messengers implicated in the process.

As such, the genetic changes from antagonism versus agonism are likely inverse, complex and different.

Do you have any ideas on how anti-psychotics lead to induction of DeltaFosB while dopaminergics do as well? I guess the induction of DeltaFosB with antipsychotics is a bad thing http://www.nature.com/npp/journal/v39/n3/full/npp2013255a.html

 

[serotonin2A]

CY you are thinking about these changes in a vacuum (only D2 > Fos), but no neurochemical system functions like that. In addition to the fact that other DA receptors may influence expression, DA can potentially alter Fos signaling by modulating release of a variety of other transmitters and neuropeptides. Well known examples in accumbens are Glu and GABA, but there are many other potential mediators.

 

[dopamimetic]

you are thinking about these changes in a vacuum (only D2 > Fos), but no neurochemical system functions like that.

This is a very important point imo, it took quite a while for me to understand (accept) the incredible complexity of biology and especially that everything is interconnected and any change could cause a myriad of downstream effects up to the point where we are at that system again where the change began, and so on ... I once labelled this as 'thinking in 3D' vs the simplified '2D' textbook explainations- the real, living system would then be '4D' somewhat. (And, of course, that with every 5% I learn more, there will always be 15% of what I begin to know not to know, and even much more of what I don't know not to know ......)

I know it's easy to complain as a layman, but I really feel that we have real problems here in everyday psych doc settings. There are these imaginations of over-simplified neurons, receptors etc. printed on SSRI advertisments that get handed out, and while simplification is required, it appears to me that quite some professionals begin to forget what they once studied (and, with all respect, having studied something doesn't always mean also to understand it) and use these oversimplifications too (what is completely understandable imo, we're all humans, but it's contraproductive). Ask your psychiatrist about the interactions of dopamine and glutamate, or DeltaFosB, whatever - you get it. It's not their matter, yes, but it should be because fuck they are the only ones who decide about what one gets prescribed and what not.. it shouldn't be up to me as a patient to inform myself about the science, double check all the things and argue with doctors, only to be thrown out of their office (what is understandable too, to some extent, as it's not the fault of a single person but of the system / structures, too less time, whatever).

Recently looked through some exam books for psychiatry at the book store, so recent edition of what one needs to know to become a doc - and well, I was a bit shocked..okay, more than a bit. Can it be for real that practicing doctors out there would have to read up to understand the discussions here? (Yes, it is. Or?)

--

This brings me again to the idea of a 3D interactive neuroscience visualization. Would still be a heavy simplification, but current technology is powerful enough by far to do some nice simulation of the current knowledge, where you could somehow enter exact these questions - e.g. add a dopamine antagonist, and then look at DeltaFosB to see what happens. Increase/decrease dosage, speed/time, and so on.. (Sorry if this isn't understandable, have to find better words.. I'd love to start such a project but I'm years behind with IT and was never good with 3D programming..)

 

[aced126]

When a drug alters gene expression, obviously the effects if any are going to be different in each gene and with each drug, but what exactly do the genes do differently after their "expression" is altered by the administration of a drug molecule? I know a gene only codes for the biosynthesis of a particular protein, such as those that make up our bodily morphology, so when a gene's expression is altered that means it produces more or less or no proteins than it would have had it been untouched by by the drug's effect?

A gene can start to be expressed more, meaning that more copies of the respective protein it codes for will be synthesised. Likewise the gene can be downregulated and less of it will be translated and coded into proteins. As an example, a compound like a drug might cause an increase in a certain biomolecule within the cell (say after activating a receptor) which will then bind onto a part of DNA and block that part from being translated and transcribed. This would be gene downregulation.

 

[PINKoPANaTHER]

Do you have any ideas on how anti-psychotics lead to induction of DeltaFosB while dopaminergics do as well? I guess the induction of DeltaFosB with antipsychotics is a bad thing http://www.nature.com/npp/journal/v39/n3/full/npp2013255a.html

I think S2A basically responded the way I would. The complete picture of how that happens would likely be worthy of a PhD thesis, but as I see it, when you alter levels of a neurotransmitter, like dopamine or others similar (that activate g-protein coupled receptors rather than ligand gated ion channels) it causes changes in the activity of the g-protein by phosphorylating the GDP attached to the g-protein (in many cases, though GPCRs have many isoforms as well) allowing it to mobilize away from the receptor and alter the effects of other ion channels. In order to return to baseline, often GTPases are activated that cleave the extra phosphate group off the g-protein, allowing it to re-bind in complex with the GPCR. Between activation of the GPCR and return of g-protein to the complex, other proteins are affected, and the more often and severe these alterations become, the more it effects other systems, for example, dynorphin levels are altered decreasing the reward effects of increased dopoamine transmission and receptor binding. Downstream a few steps from the GTPase is the transcription factors that regulate expression of receptor complexes and receptor regulating proteins more importantly. By forcing a change in the transcription factors several steps away from an increase/decrease of dopamine activity, all the genes in that cell regulated by the txn factors are affected. There is obviously a lot of information left out of this explanation, because I simply do not know it, but the basic process for genetic expression changes from paracrine and endocrine signalling basically is to that tune.

I would suggest looking up androgen receptor dynamics for a simplified model, because testosterone and other sterols are membrane soluble, their receptors are actually transcription regulation complexes attached to the gene rather than on the cell surface. This is a large reason the effects take so long to be noticeable, it causes slow changes in the way genes for nitrogen balance, anabolism, NO signalling etc. are expressed (also why it is recommended to cycle and take long breaks - you are playing with your gene expression from the start)

There is also DNA methylation, and chromatin remodeling (acetylation, methylation etc.) that can cause lasting environmental changes in gene expression that are actually inheritable...

NOTE: And that's just one system... anti-psychotics likely have effects in different signalling systems, and we know dopamine stimulants, or drugs in general often have complex neuromodulating activity through 5'HT, NE, and DA (plus others frequently).

There are some good papers on google scholar, and linked through the wikipedia page on Fos proteins, and DeltaFOSB specifically (search for deltaFosB addiction - or - deltaFosB dopamine and use a cut-off date of 2008 at the oldest for good up to date info) If you don't use keywords with the protein name you will likely get a lot of info on how it controls cell proliferation, differentiation and development.