Do anti-psychotics affect gene expression like DeltaFosB?

[PINKoPANaTHER]

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.

Actually most regulation happens before translation - the miRNA example is one of the few processes that actually regulate translation. Typically genes are regulated by the number of mRNA transcripts, and the stability of those transcripts (the poly-A tail usually determines the lifespan of an mRNA).

 

[aced126]

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..)

Agreed, in an ideal world they shouldn't really be able to prescribe medicines without having a sound knowledge of the principles behind them, even if the principles are still not well understood.

 

[Seppi]

Nonselective DA antagonists probably would not repress ΔFosB in D1-type MSNs in the striatum (caudate/putamen/nucleus accumbens), but they would unequivocally prevent further ΔFosB induction through dopamine receptor signaling in these neurons; that's the most significant signal transduction pathway involved in inducing ΔFosB expression in D1-type striatal medium spiny neurons.

Edit: it appears that D2 antagonists promote ΔFosB induction in D2-type striatal MSNs though. For example, see the entry for Haloperidol in http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834048/table/T1/

 

[serotonin2A]

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..)

We don't have enough experimental data to do what you are suggesting.

As an example of the difficulty posed in modeling the brain (or even a small part of it), consider the nematode brain. The brain of C elegans contains 302 neurons and the entire "connectome" has been mapped. But even though scientists have mapped out the structure of the nematode brain, no one has been able to accurately simulate how the nematode brain functions. One problem is that we don't know enough about factors such as non-synaptic volume transmission. But in any event, if we can't even accurately simulate a very small brain, there is no way that we can simulate a mammalian brain.

 

[Cotcha Yankinov]

Okay guys what the hell is this http://www.ncbi.nlm.nih.gov/pubmed/18848971 http://www.ncbi.nlm.nih.gov/pubmed/24829091
My precious Valproic Acid and anti-psychotics are making the same changes in the brain that addicting drugs make?
I assume then that HDAC promoters (Maybe I'm retarded and there is no such thing) are a potential treatment for addiction?

Looks like there is hope for 5-HT3 and 5-HT2 antagonists in treating addiction sensitization however http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3113440/
Here is human study showing 5-HT3 antagonism is effective for treating cocaine addiction http://www.ncbi.nlm.nih.gov/pubmed/16631323/
And another study showing 5-HT3 antagonism can change abnormal NMDA/AMPA and behavioral sensitization in rats after cocaine http://www.ncbi.nlm.nih.gov/pubmed/16794574

Ondanestron showing variable efficacy for alcohol dependence depending on 5-HTTLPR polymorphisms but somehow no significant results for men http://www.ncbi.nlm.nih.gov/pubmed/25212749

Why don't we see more use of Ondanestron to treat addiction? Does it just not perform that well or are our medicinal practices catching up to the literature?

 

[Seppi]

Okay guys what the hell is this http://www.ncbi.nlm.nih.gov/pubmed/18848971 http://www.ncbi.nlm.nih.gov/pubmed/24829091
My precious Valproic Acid and anti-psychotics are making the same changes in the brain that addicting drugs make?

No. Addiction is mediated by overexpression of ΔFosB only in D1-type NAcc MSNs. The statement that "drug X increases ΔFosB in the striatum" is far too general to conclude that something is addictive. Everything in the table that I linked in my comment increases ΔFosB in different neuronal subpopulations within the striatum, but only half the stimuli listed are actually addictive.

I assume then that HDAC promoters (Maybe I'm retarded and there is no such thing) are a potential treatment for addiction?

No, HDAC inhibitors (class I HDAC inhibitors specifically, which means butyric acid and valproate, which are mentioned in the studies you linked) are actually potential treatments for addiction, not HDAC inducers. Epigenetic modifications in addiction are complex because the time that an HDAC inhibitor is used relative to the time an addictive drug is used (e.g., prior to use, concurrently, or after a drug has cleared the body) strongly affects the expression profile for transcription factors and epigenetic proteins in the striatum.


Just to clarify this point: addiction and dependence are not the same thing. The former refers to compulsive drug use that is mediated through positive reinforcement and sensitized incentive salience; it's a disease one experiences only while they are currently under the effects of a psychoactive addictive drug. The latter refers to the development of withdrawal symptoms upon cessation of drug use, where subsequent drug use is mediated through negative reinforcement; this is a disease one experiences only when a drug has mostly or entirely been cleared from a user's body.

 

[Cotcha Yankinov]

No. Addiction is mediated by overexpression of ΔFosB only in D1-type NAcc MSNs. The statement that "drug X increases ΔFosB in the striatum" is far too general to conclude that something is addictive. Everything in the table that I linked in my comment increases ΔFosB in different neuronal subpopulations within the striatum, but only half the stimuli listed are actually addictive.

I guess I wasn't implying that the HDAC inhibitors were addicting but I'm rather wondering if you would see increased locomotor activity and such after HDAC inhibitor (Or antipsychotic) withdrawal/receptor normalization because of DeltaFosB sticking around. Sorry I didn't differentiate between a real state of addiction and rather residual sensitization/locomotor activity. I mean if HDAC inhibitors potentiate amphetamine induced locomotor activity you would think HDAC inhibitors could induce some degree of sensitization on their own. Also, regarding the population of MSNs, is the locomotor activity from DeltaFosB induction in D1 type NAcc MSNs? Because then it would seem that HDAC inhibitors would indeed potentiate addiction (as far as concurrent administration with an addicting stimulus) if they potentiate locomotor sensitization.

the time that an HDAC inhibitor is used relative to the time an addictive drug is used (e.g., prior to use, concurrently, or after a drug has cleared the body) strongly affects the expression profile for transcription factors and epigenetic proteins in the striatum

So you think the study finding that HDAC inhibitors potentiate DeltaFosB induction with amphetamine should have had a group of rats that were given only HDAC inhibitors and checked DeltaFosB levels, and you might predict that that group's DeltaFosB would be decreased compared to control?

If HDAC inhibitors potentiate DeltaFosB induction while being administered concurrently with an addicting stimulus then wouldn't a good idea be to give addicts who are still using HDAC promoters?

 

[Seppi]

Locomotor activity is modulated by the NAcc core and dorsal striatum. I'd expect ΔFosB induction in D1-type MSNs in the dorsal striatum to promote locomotor activity and inhibit locomotor activity in D2-type MSNs, based upon its role in levodopa-induced dyskinesias (see https://en.wikipedia.org/wiki/FOSB#Other functions in the brain). I'm not really sure about ΔFosB in the NAcc core, but I'd suppose that either the relationship between ΔFosB in the NAcc core and locomotor activity is similar to what I've described in the dorsal striatum or that there's no relationship between ΔFosB expression in the NAcc core and locomotor activity.

I have no idea what a class I HDAC (i.e., HDAC1, HDAC2, HDAC3, and HDAC8 ) inducer used concurrently with an addictive drug would do; however, even if they did beneficially affect ΔFosB expression, I doubt these would be used in humans because there's a very strong inverse relationship between global HDAC1 and especially global HDAC2 expression in the brain and cognitive function. You'd basically need to inject an HDAC inducer directly into the striatum to circumvent this problem.

 

[PINKoPANaTHER]

^Plus, unless the HDAC modulator was VERY specific to the regions you're trying to modulate, there could be a litany of other consequences, as every cell has histone mediated gene expression regulation. Exogenous HDAC de-regulation is also strongly correlated with oncogenesis (though the work is just beginning to flourish). HTLV-1, a retro-oncovirus mediates its effects on creating lymphoma/leukemia via histone dynamics, both transcriptinal and post-translational like an HDAC, though through induction, not inhibition like Seppi suggests.

I would be interested to see what some of the experimental (very potent and specific) HDAC inhibitors/inducers would do outside of mammalian cell culture (in higher organisms like humans), but to my knowledge, most are pretty toxic due to having effects in all cells.

I have a very distinct feeling that even as we humans uncover the mysteries belying addiction/dependence that things may not change so much (taper, abstain, form a support group, exercise etc.) because interfering with fundamental systems like Fos proteins and histone modifications will be so hard to control on the scale of an entire organism that cannot be sacrificed for histology slides after treatment...

NOTE: Acetyl groups on nuclear core particles (assembled genes+histones) results in decreased occupancy and therefore easier acccess for txn factors/polymerases allowing increased expression of the genes, which is one mechanism through which oncogenesis might occur (through disinhibition of oncogenes, which is hard to overcome with simple increases in tumor suppressor genes)

 

[Seppi]

I would be interested to see what some of the experimental (very potent and specific) HDAC inhibitors/inducers would do outside of mammalian cell culture (in higher organisms like humans), but to my knowledge, most are pretty toxic due to having effects in all cells.

Class I HDAC inhibitors are used quite regularly in medicine. Some examples include butyric acid/butyrate salts, valproic acid, trichostatin A, and vorinostat. The latter 3 are FDA-approved drugs. The 1st is used in cancer therapy and is produced within the human body; it has essentially no toxicity since it's a dietary short-chain fatty acid.

 

[Cotcha Yankinov]

I'd expect ΔFosB induction in D1-type MSNs in the dorsal striatum to promote locomotor activity and inhibit locomotor activity in D2-type MSNs, based upon its role in levodopa-induced dyskinesias

Sorry do you mean DeltafosB induction in D2-type MSNs might be expected to inhibit locomotor activity? Because that's confusing...

Okay so sorry for nitpicking but I'm still confused in regards to whether HDAC inhibitors promote or reduce DeltaFosB, because it seems from one study that solely HDAC inhibitors promote DeltaFosB. We have this study http://www.ncbi.nlm.nih.gov/pubmed/18848971 - "repeated treatment with BA or VPA produced amphetamine-like effects: enhanced cAMP responsive element binding protein (CREB) phosphorylation at Ser(133) position and increased DeltaFosB protein levels in the striatum. Furthermore, co-administration of BA or VPA with amphetamine produced additive effects on histone H4 acetylation as well as CREB phosphorylation in the striatum." We also have this study which isn't as clear and I wish I had the full study but I guess its what we've got http://www.ncbi.nlm.nih.gov/pubmed/24829091 And then of course there are other studies supporting the use of Valproic Acid and such in addiction models, which from one study seems to be related to it's GSK3B effects.

Any reasons to void these studies or interpret them carefully? I'm still confused about the whole timing of the HDAC inhibitor thing - My question is what if we're dealing with a constant dopaminergic stimulus that you might see with something like schizophrenia, or something more behavioral/thought pattern related (Chronic stress has been shown to induce DeltaFosB as well). HDAC inhibitors would be expected to worsen induction of DeltaFosB then right?

 

[aced126]

No. Addiction is mediated by overexpression of ΔFosB only in D1-type NAcc MSNs. The statement that "drug X increases ΔFosB in the striatum" is far too general to conclude that something is addictive. Everything in the table that I linked in my comment increases ΔFosB in different neuronal subpopulations within the striatum, but only half the stimuli listed are actually addictive.

No, HDAC inhibitors (class I HDAC inhibitors specifically, which means butyric acid and valproate, which are mentioned in the studies you linked) are actually potential treatments for addiction, not HDAC inducers. Epigenetic modifications in addiction are complex because the time that an HDAC inhibitor is used relative to the time an addictive drug is used (e.g., prior to use, concurrently, or after a drug has cleared the body) strongly affects the expression profile for transcription factors and epigenetic proteins in the striatum.


Just to clarify this point: addiction and dependence are not the same thing. The former refers to compulsive drug use that is mediated through positive reinforcement and sensitized incentive salience; it's a disease one experiences only while they are currently under the effects of a psychoactive addictive drug. The latter refers to the development of withdrawal symptoms upon cessation of drug use, where subsequent drug use is mediated through negative reinforcement; this is a disease one experiences only when a drug has mostly or entirely been cleared from a user's body.

Surely when the drug is cleared from the body, there are still downstream reinforcing effects?

 

[BasX]

Interesting thread. If you are interested in the drug sensitization aspect of DeltaFosB you should also read a few studies on DeltaJunD. Some studies show potential treatment of DeltaFosB mediated changes in plasticity with increases of DeltaJunD expression using viral vectors and some medications. However if I remember correctly the changes in DeltaJunD expression using drugs are currently permanent.

 

[Cotcha Yankinov]

Surely when the drug is cleared from the body, there are still downstream reinforcing effects?

Long abstinent MDMA users have increased dopamine somehow - serotonin2A thought this might be a form of sensitization.

I have read that DeltaFosB causes branching out of the dendritic processes of dopamine neurons - surely this change would stick around for a while?

 

[Seppi]

Sorry do you mean DeltafosB induction in D2-type MSNs might be expected to inhibit locomotor activity? Because that's confusing...

D2-type MSNs inhibit locomotor activity. It's an inhibitory set of neurons.

Okay so sorry for nitpicking but I'm still confused in regards to whether HDAC inhibitors promote or reduce DeltaFosB, because it seems from one study that solely HDAC inhibitors promote DeltaFosB. We have this study http://www.ncbi.nlm.nih.gov/pubmed/18848971 - "repeated treatment with BA or VPA produced amphetamine-like effects: enhanced cAMP responsive element binding protein (CREB) phosphorylation at Ser(133) position and increased DeltaFosB protein levels in the striatum. Furthermore, co-administration of BA or VPA with amphetamine produced additive effects on histone H4 acetylation as well as CREB phosphorylation in the striatum." We also have this study which isn't as clear and I wish I had the full study but I guess its what we've got http://www.ncbi.nlm.nih.gov/pubmed/24829091 And then of course there are other studies supporting the use of Valproic Acid and such in addiction models, which from one study seems to be related to it's GSK3B effects.

Any reasons to void these studies or interpret them carefully? I'm still confused about the whole timing of the HDAC inhibitor thing - My question is what if we're dealing with a constant dopaminergic stimulus that you might see with something like schizophrenia, or something more behavioral/thought pattern related (Chronic stress has been shown to induce DeltaFosB as well). HDAC inhibitors would be expected to worsen induction of DeltaFosB then right?

Interpret these studies carefully. There are a lot of things that modify the effect of HDAC inhibitors on transcription. I can't even remotely guess how HDAC inhibitors might affect someone with schizophrenia.

 

[Seppi]

Surely when the drug is cleared from the body, there are still downstream reinforcing effects?

I suppose I simplified the explanation a bit too much. Primary positive reinforcement from the drug itself does not occur when the drug is not present in the body. Secondary positive reinforcement does occur through drug cues (e.g., the sight of a crack pipe or needles can positively reinforce drug use), however.

 

[Cotcha Yankinov]

I guess I didn't think about the matter of DeltaFosB increasing the strength of inhibitory neurons. So for all we know that increase in DeltaFosB that we saw with valproate could be mainly in D2 MSNs, like it is with anti psychotics?