HOW GABAA RECEPTORS ARE CREATED AND BENZO INDUCED CHANGES

[[Pe...]]

Hi Pers, lots to consider here.

 

You may interested in the following:-

"Epigenetic mechanisms in stress and adaptation". PDF available at:-

 

http://www.aipro.info/drive/File/Epigenetic%20mechanisms%20in%20stress%20and%20adaptation%20-%20K.R.%20Mifsud%20et%20al..pdf

 

Wow iHope, this looks really good...I am trying to stay focused in order to continue to work on the Glutamate Hypothesis...but this looks really fascinating, lol...

 

Guess I will have see how good my mind is at multi-tasking 

 

I will try to read through it while I am working on my other project.

[[Be...]]

After reading through this thread and digesting as best I could the information, with just my background education in lower level college courses in Microbiology, Anatomy and Physiology, Chemistries, etc.--I got a degree in Medical Laboratory Technology; I want to ask this question?  First I want to share what my understanding is so far.  When we go into tolerance w/d, we are activating a different chromosome to create different GABA receptors which pop up to counter the benzo and which are less sensitive to GABA, per that rat experiment I read about with Chromosome 15, switching etc.  Also, the GABA receptors that were downregulated will be destroyed or recycled and the ones that are recycled will come back up in an altered form.  Where is the research that these altered receptors revert back to their original form?  Also, are we making new, is it native or pristine?, GABA receptors that are the same as when we were born?  Or are we just going to get the upregulated recycled ones and those created by a different chromosome?  And we need to live with those?  Are we going to live with three different types of GABA receptors now?  Or will our body discard the other chromosome receptors that aren't being created now since the benzo's are out of our system and we aren't in tolerance w/d?  Is this part of the explanation why people are left with heightened sensitivity to stress?  I'm alway thinking again about this DNA damage in genetically vulnerable and unlucky people?  It sounds like the real damage starts when when you go into tolerance w/d.  Is neuroadaptation just saying that we might as well get used to the "new" me? I always want to find the truth and get to the bottom of things, especially what this drug has done to me.

[[ih...]]

You ask some excellent questions,BB & hopefully between us, we can find some answers.

I'm currently not aware of any research addressing epigenetic changes in GABA receptors over the medium to long term after benzo use but Pers is a wealth of info as are others on this thread.

 

Pers, i will be interested to see what u come up with on the GLU side as clonidine was the biggest contributor to a reduction in my wdwl sx & there is evidence that it modulates glutamate toxicity, if not directly antagonising GLU receptors. I suspect that the GLU is at least 50% of the wdwl sx for many.

 

You have probably read most of the studies I have but i will post my list relevant to GLU when I get around to it.

[[ge...]]

I don't understand the science, but this is an upsetting theory for those of use who have rapid tapered or cold turkeyed. It makes me wonder if reinstatement and doing a slow taper would make sense.

 

This is clearly a 'benzo thought', but nonetheless, it's scary to read stuff like this after you have CT or rapid tapered and still symptomatic.

 

Hi gettingthere,

 

I understand how you feel because I am in the same boat.  However, this is really nothing new as most of us became aware after the fact that a CT or rapid detox has been connected to protracted withdrawal syndrome.  Bart’s suggestion simply provides a reasonable explanation as why it happened.

 

His suggestion should actually do the opposite and bring you a greater peace of mind about it all because as I just told Perseus in my post above, these changes are a form of neuroplasticity and-

 

“they are adaptive changes, where the body uses its own set of tools to adjust to changing conditions. Everyone's bodies make these types of changes all of the time to adjust to everything from changing hormone levels to adjusting to stress and anxiety.  Of course the changes in our case were more profound, but I am trying to show people that the body has the capability to reverse these changes.”

 

Your brain up and down regulates things all of the time, and receptors are absorbed and reinstated as a part of normal plastic processes.  The ‘short cuts’ may have made some slight alterations in nucleotide and thus amino acid changes- but as time wears on I should think that there would be a turnover of the receptors which should eventually bring it all back to normal.

 

The way I look at what Bart said is that- ok, we might have receptors that were made slightly different because of short cuts- but eventually they should all turn over as the neuron brings things back to status quo.  It is just going to take a long time.

 

I don’t think you will get the results you are looking for by reinstating if researchers are right about the Glutamate Hypothesis.  I am currently delving into this new topic and plan to post a separate thread on it in the future.

 

What I have ascertained so far from the little I have read, is that after you stop taking benzos there is a silent and then an active phase.  Once the active phase begins, something changes with the Glutamate side of things.  After that sets into motion taking more benzos will not completely relieve the sxs- like after it starts it sets the point of no return for reinstatement.  Researchers noted that the actual WD sxs did not commence until the active phase was set into motion.

 

This may explain why some people’s sxs don’t show up immediately after they discontinue the drug—in fact there have people who claimed it took weeks to a month or more after stopping their benzo before sxs began to appear- well beyond the half-life of the particular benzo they were taking.  That might have been due to the silent phase.

 

It also may explain why there appears to be a window of time where you can somewhat successfully reinstate (during the silent phase) and why that window of time expires (when the active phase begins).

 

Another thing it may also explain is kindling- as each attempt may set more Glutamate receptors into the active phase.

 

That is my take on it from the little I have read.  But as you can see- reinstatement could likely cause more problems for you- by changing more GABAARs and perhaps sending more Glutamate receptors into active phase.  The anecdotal evidence supports this.  Time and time again I have seen people reinstate only to be completely surprised that they were still experiencing WD sxs and then devastated realizing that they had to start all over again.

Becks, pers talked about possible chsnges in genetics during tolerance and how they are reversible so no one is 'stuck' with permanent damage. Changes might be made on the genetic level as the body adapts to the drug, but has the capacity to reverse the changes, as well, but that it takes a long time. Basically, since the brain is plastic, there is no reason it cant reach full healing. this is how I understand what pers is explaining.

[[Pe...]]

After reading through this thread and digesting as best I could the information, with just my background education in lower level college courses in Microbiology, Anatomy and Physiology, Chemistries, etc.--I got a degree in Medical Laboratory Technology; I want to ask this question?  First I want to share what my understanding is so far.  When we go into tolerance w/d, we are activating a different chromosome to create different GABA receptors which pop up to counter the benzo and which are less sensitive to GABA, per that rat experiment I read about with Chromosome 15, switching etc.  Also, the GABA receptors that were downregulated will be destroyed or recycled and the ones that are recycled will come back up in an altered form.  Where is the research that these altered receptors revert back to their original form?  Also, are we making new, is it native or pristine?, GABA receptors that are the same as when we were born?  Or are we just going to get the upregulated recycled ones and those created by a different chromosome?  And we need to live with those?  Are we going to live with three different types of GABA receptors now?  Or will our body discard the other chromosome receptors that aren't being created now since the benzo's are out of our system and we aren't in tolerance w/d?  Is this part of the explanation why people are left with heightened sensitivity to stress?  I'm alway thinking again about this DNA damage in genetically vulnerable and unlucky people?  It sounds like the real damage starts when when you go into tolerance w/d.  Is neuroadaptation just saying that we might as well get used to the "new" me? I always want to find the truth and get to the bottom of things, especially what this drug has done to me.

 

As iHope stated, this is what we are attempting to sort out.  I stated in my original post:

 

“Success stories offer anecdotal evidence that reversal of neuroadaptive changes can and do happen anywhere from months to years after benzodiazepine discontinuation.  When studying benzodiazepines, what most research studies consider ‘long term’ benzodiazepine treatment only tends to be anywhere from 7-32 days, and, the effects in neurons after withdrawal are examined only anywhere from 6 hours to 7 days after withdrawal has been induced. (18)  To my knowledge there have not been any long term studies examining reversals of neuroadaptations after benzo withdrawal.  Researchers make assumptions as to the reversibility of these changes based on their observations, and without long term studies, any claims regarding irreversibility of changes to gene expression would be unsubstantiated, and perhaps, reckless.”

 

I think that the way the body has really strong inclinations to continuously maintain and restore homeostasis would support the view that while these changes may take a long time to reverse- they eventually should.  It is not like a disease process was initiated of there was some kind of permanent damage, at least from what I have read.  All of the changes I have read about were plastic and are the same type that the body makes under other conditions- including our own reactions to stress, hormonal changes, etc… So I should think that it leans toward reversal and restoration of status quo.

 

Without ‘true’ long term scientific studies we have nothing in writing to support it either way- but we do have anecdotal stories where people claim full recoveries months to years after discontinuing benzos- some are like 3-5 years later, which shows that reversals of neuroadaptations can continue for many years.

 

The way the Pharmaceutical companies move on to other versions of benzos may hamper efforts in figuring out what’s what with the generation of benzos we took- as research is expensive and rehashing older medications is not lucrative like the promotion of newer versions.  Ashton was trying to get funding for research but last I heard her efforts were unsuccessful.

 

So the bottom line is that the only long term ‘evidence’ we currently have are the anecdotal stories- which support the view that reversal of neuroadaptations have continued to occur over the span of many years.  This evidence also shows that most people heal much sooner than that…I wanted to include that so no one assumes it will take years in their particular case.

 

[[Pe...]]

 

Pers, i will be interested to see what u come up with on the GLU side as clonidine was the biggest contributor to a reduction in my wdwl sx & there is evidence that it modulates glutamate toxicity, if not directly antagonising GLU receptors. I suspect that the GLU is at least 50% of the wdwl sx for many.

 

You have probably read most of the studies I have but i will post my list relevant to GLU when I get around to it.

 

I may be in over my head on this one, lol....each type of Glutamate receptor could have its own thread- these are much more involved than GABAA receptors.  It is going to be a challenge for sure to get through this next venture- which will most likely be my last one here on BBs.

 

My time is pretty limited nowadays, so I have no idea when or if I will be able to finish it- as it appears that to fully understand it all may require many months of in depth studying of Glutamate receptor function- which I don't have.  I really had no idea how involved it was all going to be.  I will keep plugging away at it little by little as I get time and see what I can come up with.

 

 

[[Be...]]

Thanks everyone and Perserverance for your comments.  I do need to think more positively about my recovery and get those receptors to straighten up and fly right.  I'm only about 6 months off and feeling symptomatic most days and depressed, so I'm seeing it all in a negative light right now.  Probably not the best time to be evaluating this info.  Seeing it in a slanted light, perhaps. 

[[ih...]]

Becks, I am in bed on day 2 of  the worst wave I have had since being off, likely due to codeine wdwl after a gastro condition with unbearable pain but am still confident that our receptors will return to business as usual eventually.

 

It fascinates me that all our sx are somewhat unique to us as individuals & though some poor souls get hit with a basket full of sx, most of us seem to have our own little subset. My bad wave sx are identical every time, POTS, (which i did hope that I had seen the back of, but not yet apparently) & benzo flu.

 

I can only assume that the codeine wdwls have thrown the switch back somehow, so will use this bedridden time to do some more research on the glutamate side of things. I know opioids surpress glutamate so maybe I now have a rebound.

[[Be...]]

I did learn that GABA is made from glutamate.  Would love to take a drug that damps down the glutamate.  I have days now when I feel eerily calm and connected but yet overstimulated.  I guess it's just my GABA and glutamate trying to even itself out and my receptors busy doing fine tuning, I hope.  I feel too much glutamate though and can hear a pin drop.  Don't like it.  I want my original receptors and neurotransmitters back I had when I was a kid.

[[Bi...]]

YOU SAID;

 

may explain why reinstatement does not always take away all of the withdrawal symptoms, why it must be done within a short window after the drug was initially discontinued, and may be what is behind the kindling phenomenon.

 

I was off for 8 months c/t.  When I reinstated at the old high dose it did not work.  My benzo Doctor expert said "YOU HAVE TOO HIT IT HARDER"  This meant I had to take even higher doses for a few weeks or I would risk PARADOX.  During reinstatement I was on up to 12 mg Ativan per day, it worked and I soon got down to 4 mgs with a nice landing and started tapering from there.

 

NOTE: This takes an expert and lots of Doctor monitoring.  Many reinstatement's fail since they are too under-medicated for such a long time off.  It takes higher doses for a short term to reinstate properly so my benzo doc told me and for valium patients they have to take even more to get the Valium saturation period down faster.

 

Just for  FYI purposes.

[[Pe...]]

Birdman,

 

Keep in mind that I am not done yet with the Glutamate Hypothesis- but so far from what I have read, this is my take on what could have happened.

 

The CT would cause a relatively sudden chloride deficiency.  This lack of hyperpolarizing chloride would cause a state of depolarization.  The depolarization would then activate NMDA receptors by initiating a voltage dependent release of the magnesium ions from NMDA receptor binding sites.  The activated NMDA receptors would in turn allow an influx of Calcium ions.

 

The influx of Calcium would then activate Ca2+/calmodulin-dependent protein kinases II (CaMKII).  The CaMKII would then phosphorylate the AMPA receptors enhancing their activity and cause an increase in the number of AMPA receptors on the cell surface.  This could result in Long Term Potentiation (LTP), causing an increase in the synaptic response to a baseline stimulus.

 

Remember all this sets into motion AFTER you CT’d.  So now you have all this action set into motion on the Glutamate side of things-taking your original dosage may not be enough to mediate it and you would need a larger dose to combat this increase in excitatory activity.

 

Here is a quote from one of the articles I was just reading that explains this in other terms:

 

“Activity-dependent changes in synaptic function are primarily the consequence of intracellular Ca2+-dependent biochemical cascades and involve changes in synaptic AMPAR number and/or function (Hayashi et al, 2000; Song and Huganir, 2002). A GABAR-mediated depolarizing potential, which is present in 2-day FZP-withdrawn CA1 neurons (Zeng et al, 1995), has been shown to activate NMDARs (Staley et al, 1995) and may contribute to increased postsynaptic Ca2+-mediated signal transduction. Thus, in the context of BZ withdrawal, the initial trigger for AMPAR upregulation, though as yet unidentified, may also involve Ca2+-mediated mechanisms similar to that which occur during other forms of activity-dependent neuronal plasticity (Nestler, 2001b).”

 

http://www.nature.com/npp/journal/v29/n11/full/1300531a.html

 

That’s my take on it from what I have read so far--- but I am in the beginning stages of learning about this hypothesis.  Perhaps others here could jump in and give their opinions or corrections if I have misinterpreted this.

 

[[ih...]]

I agree with Pers's Interpretation of the literature & it also seems to be consistent with what your MD is saying.

 

Its great that you were able to drop back your dose again so quicly, Bird.

[[li...]]

Perseverance, if I may 'break' into this thread.

 

It's about benzo induced changes, anyway.

 

As a side note, I don't have a real doc, just a GP playing doctor (we can't just choose or buy medical care here) and a pharmacist who suggested that I could get off this drug in two, at most four weeks (!) because I was not 'addicted' even though I've been taking the stuff for about 10 years !

That's the level of care here, and since I don't have a fortune to spend I'm mostly on my own.

You have to approach the doc like a small child, and treat the doc like a big child

Not to mention the prejudice and overwhelming ignorance/arrogance ...

 

Anyway, to the point:

 

Since I won't be off soon unless I do a C/T I do have to exercise since I'm in very bad shape.

The name of my poison is clonazepam. Recently I exercised (big mistake?) and I may have overactivated the CRH neurons or expressed CRH levels. A single bout of exercise can have effects that last for about two weeks.

It's like this: exercise shifts the sedating properties of clonazepam to stimulation. Actually, last time the real (mental) stimulation started after I took the drug !

A few points: the exact effects of this drug greatly depend on the time of day I take it.

Regarding exercise, higher doses seem to minimize the neurological (and mood) effects to a point while stimulating gluconeogenesis, including cortisol production. Lower doses seems to minimize glucocorticoid production while greatly exaggerating neurological effects (insomnia, experience of time slowing down after strenuous exercise, feeling you're crashing into a concrete wall). This is not entirely new, but much worse than years ago.

 

Today, and yesterday I felt a cortisol surge (probably general gluconeogenesis as well) at 7 to 8 PM. That didn't bode well for sleep and functioning for the next days.

 

Let's say I improvised, take an extra dose and using some alcohol for sleep.

 

I should be ahead of evening cortisol surges. I'm fairly sure CRH (gene expression) is involved.

Any suggestions ? Time may help but on its own that can take two weeks ...

 

I know your not a doc, but do you have any ideas ? Drug treatment or otherwise ...

 

(Professionals here are very 'benzo UNWISE' and I'm not even referring to the Ashton protocol. I have noticed that I can forget about bringing any scientific material, they won't even look at it ...)

 

Back to the cortisol issue (which probably represents stress so it will cause host of other problems):

Any suggestions about how to deal with it ? Cortisol is not bad, but massive evening cortisol surges are. Pretty sure it has to do with CRH or other systemic effects.

It doesn't have to be natural, what is natural about this drug ?

 

Replies from other people are welcome too of course.

 

What I'm taking usually is closer to 1.5 1.75 mg, rarely more to 'stabilize'.

[[Bi...]]

Thanks Perseverance and Ihope

 

Hey liberty, did you ever think of getting on Ativan?  I think its milder than K and the 20 hour half life is kind of ideal for once per night dosing and waking up not feeling overly Zonked .  By bed time the next night you can feel the need for it again as the tension builds once again. But I have to say the sleep is good doing it this way!!  I am trying to cut so slow that I only need one dose at night.  Many people say its possible if done slow enough.  I am sure that at around 1mg it will fall apart and I'll have to go to the dreaded Valium again and not sleep for the first week at all as my HP-axis gets an adjustment.

 

[[Pe...]]

Does anyone here have the ability to access the full text (complete article) of this abstract?

 

https://www.ncbi.nlm.nih.gov/pubmed/19524526

 

This could be important to the Glutamate Hypothesis that I am currently researching.  I would really appreciate any help.

[[Na...]]

I am new here and just joined after I read some very illuminating posts.

 

To Perseverance or anyone else.

 

is it possible that consuming foods that are higher in Glutamate may produce a quicker up-regulation of GABA receptors as the brain is trying to reach equilibrium?

 

From personal experience I can tell you that i get fasciculations (muscle twitches) when i eat glutamate rich foods ( ie nuts) which reminds me of the acute stages of BZ WD.

 

 

[[he...]]

Perseverance, I do believe totally that the glutamate has a big factor in all this, I myself had a test done C4a , which indicates high cellular inflammation , mine was off the charts, I feel like I am full of chemical toxins, I am in extreme pain, all over its actually worst then I ever endured before, I myself is just hit 3 years in May , and I have increasingly got worst, everything I eat makes it 100xs worst, I am under tremendous amount of stress, my husband left me, my kids are conspiring with my husband to sabotage my company , financially I am going down hill, I am severe severe pain , and feel extremely hopeless , but I do believe strongly about the glutamate is effecting all this, I had a glutamate test done it came back high high high, I had it done by a NP Dr , it was tested by my saliva , IDK if its any validation. I would like to know more on your study of Glutamate . thanks

[[Pe...]]

I am new here and just joined after I read some very illuminating posts.

 

To Perseverance or anyone else.

 

is it possible that consuming foods that are higher in Glutamate may produce a quicker up-regulation of GABA receptors as the brain is trying to reach equilibrium?

 

From personal experience I can tell you that i get fasciculations (muscle twitches) when i eat glutamate rich foods ( ie nuts) which reminds me of the acute stages of BZ WD.

 

 

 

Hi Naturalhealing,

 

The Glutamate side is already ramped up from discontinuing benzos, so if anything I should think it may just cause more excitability.

 

There are many factors that regulate Chloride equilibrium in the neuron such as intracellular chloride-dependent chloride channel ClC–2, the Potassium-chloride transporter member 5 (aka: KCC2 and SLC12A5), and the sodium-potassium-chloride co-transporter 1 (NKCC1)--so as you can see it is much more complex than that.

 

Also the subunit configuration of the GABAA receptors may be changed too--simply adding Glutamate to the equation is not the answer- too bad it is not that simple right?

 

A lot of people are sensitive to foods containing MSG- but I have not heard of sensitivities to foods naturally high in Glutamate.  However, I never discount anything after what I have seen around here and experienced myself- stranger things have happened.

 

 

 

[[Pe...]]

Perseverance, I do believe totally that the glutamate has a big factor in all this, I myself had a test done C4a , which indicates high cellular inflammation , mine was off the charts, I feel like I am full of chemical toxins, I am in extreme pain, all over its actually worst then I ever endured before, I myself is just hit 3 years in May , and I have increasingly got worst, everything I eat makes it 100xs worst, I am under tremendous amount of stress, my husband left me, my kids are conspiring with my husband to sabotage my company , financially I am going down hill, I am severe severe pain , and feel extremely hopeless , but I do believe strongly about the glutamate is effecting all this, I had a glutamate test done it came back high high high, I had it done by a NP Dr , it was tested by my saliva , IDK if its any validation. I would like to know more on your study of Glutamate . thanks

 

Sorry to hear all this Laura.

 

I just sent off an email to a PhD who is working research regarding the Glutamate Hypothesis asking a bunch of questions.  This research team is really on the cutting edge so let's hope I get a response.  I am working on this little by little each day as time permits.  From what I have learned so far I believe that the Long Term Potentiation of the AMPA receptors created by benzo discontinuation may be a reason behind protracted symptoms.  That was one of the questions I asked.

 

I also asked if they thought phosphorylation might be responsible for windows and waves.

 

I will let everyone know if I get a reply.

 

 

[[Kr...]]

I just sent off an email to a PhD who is working research regarding the Glutamate Hypothesis asking a bunch of questions.  This research team is really on the cutting edge so let's hope I get a response.  I am working on this little by little each day as time permits.  From what I have learned so far I believe that the Long Term Potentiation of the AMPA receptors created by benzo discontinuation may be a reason behind protracted symptoms.  That was one of the questions I asked.

 

I also asked if they thought phosphorylation might be responsible for windows and waves.

 

I will let everyone know if I get a reply.

 

I'm really interested in this as I suffer from restless legs syndrome which recently has been attributed to excess glutamate in the brain.  I really appreciate your research on this!

[[Mo...]]

 

HI;

 

wow thank you very much indeed just found this thread.

really impressing

thanks

Ig

[[ih...]]

Great going on finding the PhD team, Pers,. Let me know if there's any discrete aspect I could look at for you.

[[Be...]]

I noticed the term phosphorylation popping up in reference to w/d and just wanted to mention that of all the blood tests I had done while in tolerance w/d, the one test that came up positive was an antibody called Anti Beta2 Glycoprotein 1 (IGM) which is an antiphospholipid antibody.  I noticed the phosphate in both the phosphorylation and the antiphospholipid.  I believe the s/x's we are having from w/d is an antibody response to our altered cells.  It makes sense.  I think my calf cramps and RLS are also related to this.  I was diagnosed with Thrombophilia while in tolerance w/d.  Just wanted to throw that out there as an observation.   

[[Ba...]]

Does anyone here have the ability to access the full text (complete article) of this abstract?

 

https://www.ncbi.nlm.nih.gov/pubmed/19524526

 

This could be important to the Glutamate Hypothesis that I am currently researching.  I would really appreciate any help.

 

There you go. 

[[Pe...]]

Awesome Bak233- much appreciated!

 

ihope- thanks for the offer. I will let you know if I need your help.

 

Becksblue- I am happy to see that you are picking up on Greek and Latin root words.  However, I think these are two separate issues as the one you spoke of deals with lipids and the phosphorylation that I am talking about deals with proteins being activated.

 

Morreweg- welcome to the conversation.

 

Everyone-

 

If I don't get a response to my email after week or so- I will contact the research team by phone.  I will try to get these questioned answered if I can.