News about benzos and GABA receptors

https://www.nature.com/articles/s41598-017-15628-7

presence of an alpha subunit is not required

Hmmmm.

Am I right in understanding that this study indicates that these GabbaAR formations (B2-y2) may become the more common form of A' receptor in benzo induced conformational changes?  This is profound given the study indicates the different way that the B2-Y2 receptor is depolarized by diazepam. 

-RST

I tried, but I need this simplified.. what does it all mean?

Ditto.  Ya lost me at 'The major isoform of the GABAA receptor is α1β2γ2. '

I tried, but I need this simplified.. what does it all mean?

 

Ditto.  Ya lost me at 'The major isoform of the GABAA receptor is α1β2γ2. '

 

if we could get this in English please, thanks

You're asking me this a month after the fact !

Simply that an alpha subunit is not required for binding of (some) benzodiazepines.

And that these Benzodiazaphines can also bind to the β subunit.  If a particular subunit is getting “slammed”(ie, excessive binding by the Benzodiazaphine), the receptor subunit configuration can change over time.  This is what leads to changes is density population of certain GABAaRs with certain subunits over time(ie, downregulation),changes in extra synaptic vs synaptic distributions of GABAaRs with particular subunits, and changes in sensitivity of the GABAAR to the endogenous GABA neurotransmitter.  Endocytosis, exocytosis, and receptor trafficking are the key research topics in this area.

Also see RSTs post in an interesting drug called etifoxine on the layman’s thread.  It binds solely to the β2 subunit of the GABAAR.  It’s not officially a classical Benzodiazaphine (?) but it does reduce anxiety.

The article in this thread illustrates  how GABAaRs can be bound by Benzodiazaphines in multiple ways, and to me it implies  how receptor subunit configurations can change over time, and how these changes are very important to the Benzodiazaphine binding characteristics (ie, subunit affinities).  The α subunit apparently is not absolutely necessary for diazepam binding to the receptor which is really weird to think about.  You would think they would already know this after 60 years.

If kolonopin binds to certain subunits and phenobarbitol binds to certain subunits; ( my understanding is pheno binds to completely different sites)

if you are on both at the same time; and tapering the kolonopin first; does that mean no gaba upregulation is happening and will make it harder to taper and get off the kolonopin because the phenobarbitol is there?

And then make it even impossible to get off pheno after?

I know they are both positive allosteric modulators (PAMS)

The phenobarbitol did for me in its limited capacity what kolonopin could not due to

Pheno’s différent mechanism of action-that’s what my body responded to-

I read they synergistically work off each other - but how does that effect a taper?

Opinions greatly appreciated

And that these Benzodiazaphines can also bind to the β subunit.  If a particular subunit is getting “slammed”(ie, excessive binding by the Benzodiazaphine), the receptor subunit configuration can change over time.  This is what leads to changes is density population of certain GABAaRs with certain subunits over time(ie, downregulation),changes in extra synaptic vs synaptic distributions of GABAaRs with particular subunits, and changes in sensitivity of the GABAAR to the endogenous GABA neurotransmitter.  Endocytosis, exocytosis, and receptor trafficking are the key research topics in this area.

 

Also see RSTs post in an interesting drug called etifoxine on the layman’s thread.  It binds solely to the β2 subunit of the GABAAR.  It’s not officially a classical Benzodiazaphine (?) but it does reduce anxiety.

 

The article in this thread illustrates  how GABAaRs can be bound by Benzodiazaphines in multiple ways, and to me it implies  how receptor subunit configurations can change over time, and how these changes are very important to the Benzodiazaphine binding characteristics (ie, subunit affinities).  The α subunit apparently is not absolutely necessary for diazepam binding to the receptor which is really weird to think about.  You would think they would already know this after 60 years.

Sooo.. benzos dont work as well after a certain time. Am i understanding that correctly? Does it damage anything? We still heal dont we?

Pleasebehere,

´If kolonopin binds to certain subunits and phenobarbitol binds to certain subunits; ( my understanding is pheno binds to completely different sites)

if you are on both at the same time; and tapering the kolonopin first; does that mean no gaba upregulation is happening and will make it harder to taper and get off the kolonopin because the phenobarbitol is there?´

As I understand, pheno also affects the kainate and AMPA glutamate receptors as antagonists. I could be wrong. Benzos bind to the alpha 1,2,3,5 subunits of GABAA (we have learned since that benzos can bind to GABAA receptors without an alpha subunit, but let´s keep it simple). Pheno binds to the alpha 1,2,3,4,5,6 alpha subunit.

About your question: I guess it´s a little complicated. We can´t know for sure, but my guess is that tapering the K is most important. The amount of pheno is not that huge. Do the drugs potentiate each other ? Who knows ? I don´t have a better idea.

So the phenobarbitol and benzo are binding to the same subunits then? Pheno on one extra the subunit 6...That’s what’s confusing me...

That benzo and barbiturate are competing for the same sites? How can they both be sitting on there and noteffect each other? In spite of the research you just posted...

I thought barbiturates had their own and benzo had their own binding sites but that it was just GABA A they had in common

And yes your right pheno works on Kinaic acid  and I thought it was the nmda glutamate receptor

Sorry Liberty I’m just thinking out loud- on the theory of how this all works

And that these Benzodiazaphines can also bind to the β subunit.  If a particular subunit is getting “slammed”(ie, excessive binding by the Benzodiazaphine), the receptor subunit configuration can change over time.  This is what leads to changes is density population of certain GABAaRs with certain subunits over time(ie, downregulation),changes in extra synaptic vs synaptic distributions of GABAaRs with particular subunits, and changes in sensitivity of the GABAAR to the endogenous GABA neurotransmitter.  Endocytosis, exocytosis, and receptor trafficking are the key research topics in this area.

 

Also see RSTs post in an interesting drug called etifoxine on the layman’s thread.  It binds solely to the β2 subunit of the GABAAR.  It’s not officially a classical Benzodiazaphine (?) but it does reduce anxiety.

 

The article in this thread illustrates  how GABAaRs can be bound by Benzodiazaphines in multiple ways, and to me it implies  how receptor subunit configurations can change over time, and how these changes are very important to the Benzodiazaphine binding characteristics (ie, subunit affinities).  The α subunit apparently is not absolutely necessary for diazepam binding to the receptor which is really weird to think about.  You would think they would already know this after 60 years.

 

Sooo.. benzos dont work as well after a certain time. Am i understanding that correctly? Does it damage anything? We still heal dont we?

Hi, I hear you on the frustration.    Yes, the above is  a long winded explanation of why tolerance and dependence develops (one way, at least).  In layman’s terms the Benzodiazaphine mangles the GABAaRs.  I know a lot of people won’t like that term “mangle”, but I say it only in the context that it’s not irreversible.    Yes we heal.  I’m healing and many others have healed.   

I think PWS goes waaaaay  beyond just the receptor itself.  That where the limited receptor based model for Benzodiazaphine withdrawal and recovery falls apart.

The model presented on page 40 of the layman’s thread tries to tie in all the collateral systems involved , that lead to protracted withdrawal.  The stress system becomes very dysfunctional, and that takes a lot of time to normalize, as does the neurogenesis that naturally occurs in plastic regions of the brain.  Both of these systems are profoundly dysregulate by chronic Benzodiazaphine use.  But once these systems recover, a person’s symtoms vastly improve.  Chronic  negative stressors are one thing that  can perpetuate the symptoms, and negative stressors can lead to a relapse (which is also    Recoverable)

I hope this helps a bit

If kolonopin binds to certain subunits and phenobarbitol binds to certain subunits; ( my understanding is pheno binds to completely different sites)

if you are on both at the same time; and tapering the kolonopin first; does that mean no gaba upregulation is happening and will make it harder to taper and get off the kolonopin because the phenobarbitol is there?

 

And then make it even impossible to get off pheno after?

 

I know they are both positive allosteric modulators (PAMS)

 

The phenobarbitol did for me in its limited capacity what kolonopin could not due to

Pheno’s différent mechanism of action-that’s what my body responded to-

I read they synergistically work off each other - but how does that effect a taper?

 

Opinions greatly appreciated

Hi PBh,

These are great questions and very difficult questions.  From the other responses, it looks like everyone has read the excellent Wikipedia barbiturate citation.

It might be that the phenobarbital blockage of the kainate and NMDARs is also offering you significant symptomatic relief.  As you know, from the layman’s thread page 40,the glutamatergic system is yet another pillar that is destabilized by Benzodiazaphines.

Attenuating the membrane potential via the glutamatergic receptor block can be very dramatic.

As the Wikipedia link indicates, barbiturates can also inhibit Ca2 release of neurotransmitters (ie presynaptic release) from the vesicles.  The phenobarbital apparently does this via VGCCs.  This would offer you some additional relief.

You are asking very good questions above.  There does seem to be “crosstalk” between the PAM bindings from one subunit pair to another.  I don’t want to confuse things more, but this citation below examines such crosstalk.  I pulled the relevant quote from it below. The full pdf is available for free and this is fairly recent research, 2013

http://www.jbc.org/content/288/27/19343.full?sid=695fa68e-ce56-478a-b159-6414b4c66117

Quote

Protein microsequencing revealed that R-[3H]mTFD-MPAB did not photolabel the etomidate sites at the β+-α− subunit interfaces.

Instead, it photolabeled sites at the α+-β− and γ+-β− subunit interfaces in the transmembrane domain. On the (+)-side, α1M3 was labeled at Ala-291 and Tyr-294 and γ2M3 at Ser-301, and on the (−)-side, β3M1 was labeled at Met-227. These residues, like those in the etomidate site, are located at subunit interfaces near the synaptic side of the transmembrane domain. The selectivity of R-etomidate for the β+-α− interface relative to the α+-β−/γ+-β− interfaces was >100-fold, whereas that of R-mTFD-MPAB for its sites was >50-fold. Each ligand could enhance photoincorporation of the other, demonstrating allosteric interactions between the sites.

End quote

What all that stuff above means in English is

The barbiturate (R-[3H]mTFD-MPAB) apparently preferentially binds to 2 distinct sites on the GABAAR , α+Β- and γ+B- (alpha1beta3 and another site gamma1beta3)

R-etomidate is another PAM anesthetic that they did photolabeling testing against.  This one binds to β2s and β3s at the β+α- site.    So these two different drugs bind to distinct sites. 

There is apparently crosstalk between the two, ie one drug could affect binding efficiency of the other drug, even though they are binding to distinct sites, which was the point of the study.

For your case, Benzodiazaphines are binding primarily to alphas-gammas, α+γ-    The citation above unfortunately did not include Benzodiazaphines , but based on the study, there might be crosstalk between the barbiturate and the Benzodiazaphine is a similar manner, each one affecting the ligand binding characteristics of the other.

((((.  Note:  Neurosteroids bind to α+β-  )))))))

Also, I don’t think we can conclude that just because the alpha subunit is involved in both Benzodiazaphine and barbiturate binding that the alpha won’t be able to upregulate as you taper the clonazepam.  The barbiturate (alpha-beta or gamma-beta) and Benzodiazaphine (alpha-gamma) junction sites  are distinct binding sites on the receptor itself because of the way the subunits are arranged (wrapped) around the Cl- pore.  I don’t have a Diagram posted here, but see figure 1 in link above

What happens in terms of intracellular receptor trafficking ( ie absorbing and emergence of receptors with different subunit configurations) is something I would have to look at specifically to answer your question completely.  Will the alphas still be downregulated after withdrawal from clonazepam, as the phenobarbital is continued?  There might be some studies, similar to the one above that involve Benzodiazaphines and barbiturates and how they synergistically affect receptor trafficking intracellularly, and what happens when one or the other is flushed from the body......  That’s the area of required reaearch. 

But remember, the barbiturate studied above has distinct binding sites physiologically from the Benzodiazaphine.  I don’t know if phenobarbital is similar to the barbiturate in the study above.

Oh gosh dm123.... if u have the inclination or time to look into this further as you stated in your previous response to answer my question...I would be so forever grateful..!!!

But it keeps leading me back as to why you shouldn’t take two PAMS together; as you taper because I assumed receptors won’t upregulate?

I’m cognitively impaired so sorry if I don’t make sense or if it appears I’m repeating myself...

Deepest gratitude

Pleasebehere,

'But it keeps leading me back as to why you shouldn’t take two PAMS together; as you taper because I assumed receptors won’t upregulate?'

I know that question was not addressed to me ... and dm123 refers to one specific barbiturate ... anyway, common theory goes that barbiturates bind to alpha 1,2,3,4,5,6 meaning that contrary to benzodiazepines they also bind to alpha 4 and 6.

That questions of yours is true as a generalization. You'd be messing with the body too much. People on more than one benzo seem to have much more trouble. Actually, I was under the impression that your dose of pheno was low. I checked a few charts, I'm not so sure. You may or may not want to talk to your doc about that (doctors !). A low dose of pheno makes sense, I'd be cautious about a large one added to the pheno over a longer time. But of course you have to take into account the pharmacokinetics.

And for dm123:

'Chronic  negative stressors are one thing that  can perpetuate the symptoms, ' I'm basically dealing with the consequences of medical abuse and negligence. That's not just the benzo. In other words, problems that cause physical distress and impair daily functioning (to be nonspecific), And with this primitive healthcare system, it's very hard to get something done about that. Healthcare is restrictive, and specialists want to work they learned their job and that includes the medical habitus. Note: The Netherlands !

If you have any ideas ?

I indeed do have that uncanny feeling that this is true.

Oh gosh dm123.... if u have the inclination or time to look into this further as you stated in your previous response to answer my question...I would be so forever grateful..!!!

 

But it keeps leading me back as to why you shouldn’t take two PAMS together; as you taper because I assumed receptors won’t upregulate?

 

I’m cognitively impaired so sorry if I don’t make sense or if it appears I’m repeating myself...

 

Deepest gratitude

Hi PBH,

Any PAM mixing, regardless of binding site, will affect healing (upregulation). 

1.Most likely there is crosstalk between the two PAMs.(similar to the study above)

2. Intracellularly, where receptor trafficking is regulated (absorption of GABAaRs with particular subunits, and exocytosis of newly configured GABAaRs with different subunits) is where the research has to be.  I would think that Benzodiazaphine alone vs (Benzodiazaphine + barbiturate) would affect receptor trafficking differently, but just because it’s different doesn’t mean it’s “better” or “worse”

3.As to how the alpha unit itself is affected differently between these 2 cases is even a more complex question. 

4.given that we agree that you cannot taper both at once, I would follow your docs instructions as to how to stage the taper and which one to taper first, especially given that 2 different classes of drugs are involved.  If you were on 2 different Benzodiazaphines it would be much more straightforward. 

5.as discussed by several others and myself, the phenobarbital does affect presynaptic neurotransmitter release and glutamatergic receptors, which may be therapeutic during wd.

I hope this helps a bit

Pleasebehere,

 

'But it keeps leading me back as to why you shouldn’t take two PAMS together; as you taper because I assumed receptors won’t upregulate?'

I know that question was not addressed to me ... and dm123 refers to one specific barbiturate ... anyway, common theory goes that barbiturates bind to alpha 1,2,3,4,5,6 meaning that contrary to benzodiazepines they also bind to alpha 4 and 6.

 

That questions of yours is true as a generalization. You'd be messing with the body too much. People on more than one benzo seem to have much more trouble. Actually, I was under the impression that your dose of pheno was low. I checked a few charts, I'm not so sure. You may or may not want to talk to your doc about that (doctors !). A low dose of pheno makes sense, I'd be cautious about a large one added to the pheno over a longer time. But of course you have to take into account the pharmacokinetics.

 

And for dm123:

 

'Chronic  negative stressors are one thing that  can perpetuate the symptoms, ' I'm basically dealing with the consequences of medical abuse and negligence. That's not just the benzo. In other words, problems that cause physical distress and impair daily functioning (to be nonspecific), And with this primitive healthcare system, it's very hard to get something done about that. Healthcare is restrictive, and specialists want to work they learned their job and that includes the medical habitus. Note: The Netherlands !

If you have any ideas ?

I indeed do have that uncanny feeling that this is true.

Hi,

Yes, I only came to the conclusion of how critical the stress system was to the GABAergic and glutamatergic systems after quite a bit of research.  There was so much research in this area that I had to wrap things up in that area.  Otherwise I would not have been able to move  on to the Neural plasticity and neurogenesis aspects of Benzodiazaphine wd.

I am firmly convinced that negative stressors are one of the critical factors because stress hormones affect action potential dynamics, neuroplasticity and neurogenesis.

Regarding ideas, given how primitive medical knowledge is in this area, clinically, there are very few things other than reducing negative stressors, light to moderate exercise, normalizing the circadian rhythm, and doing a slow symtom based taper (ie, time) , to help with tolerance or wd.    These things are easier said than done, especially minimizing negative stress.  Today’s culture is very stressful in and of itself.  Enriched environment would be ideal for all of us 

dm123 You mention a ‘layman’s thread’ can you point me to it please.

dm123 You mention a ‘layman’s thread’ can you point me to it please.

Hi Ajusta,

Here is the link.  Please spread the news.  I want people to know the full truth on how these Benzodiazaphines affect our physiology. 

It’s very scientific and a bit technical.    Page 40 provides a summary of the model.  The foundation of the model is pages 1-40.  Current paper is on the neural circuit aspect of the model.  Benzodiazaphines impose a huge stressor on the normal physiological function of our neural circuits.

http://www.benzobuddies.org/forum/index.php?topic=184940.0

Dm123 and Liberty,

Thank you so much for your time and efforts in helping me so much...

No matter what I do I feel so incredibly doomed and trapped as I’ve suffered such severe neurological issues from this with no quality of life;;;;;

It all feels insurmountable - blessings to all suffering

dm123 You mention a ‘layman’s thread’ can you point me to it please.

 

Hi Ajusta,

 

Here is the link.  Please spread the news.  I want people to know the full truth on how these Benzodiazaphines affect our physiology. 

 

It’s very scientific and a bit technical.    Page 40 provides a summary of the model.  The foundation of the model is pages 1-40.  Current paper is on the neural circuit aspect of the model.  Benzodiazaphines impose a huge stressor on the normal physiological function of our neural circuits.

 

http://www.benzobuddies.org/forum/index.php?topic=184940.0

Wishful thinking, dm, in my opinion that's categorically impossible.

dm123 You mention a ‘layman’s thread’ can you point me to it please.

 

Hi Ajusta,

 

Here is the link.  Please spread the news.  I want people to know the full truth on how these Benzodiazaphines affect our physiology. 

 

It’s very scientific and a bit technical.    Page 40 provides a summary of the model.  The foundation of the model is pages 1-40.  Current paper is on the neural circuit aspect of the model.  Benzodiazaphines impose a huge stressor on the normal physiological function of our neural circuits.

 

http://www.benzobuddies.org/forum/index.php?topic=184940.0

 

 

Wishful thinking, dm, in my opinion that's categorically impossible.

It’s wishful thinking indeed, but the scattered research in this area was not helping anyone understand.  It did not help.  The research was all disconnected.  There was no cohesive model.

For me, it was a very helpful process.  I understand what happened and how it happened.    I can now move forward with this understanding in place.

Impossible?  Perhaps.  Nonetheless, the model will always continue to evolve.

Best

Dm123

Thanks for link. Finally feel up to looking at it!

Hi Ajusta,

I hope it helps a bit.  I hope it gives you the same insight that it has given me, in writing it.