Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: ...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/

 

"Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?"

 

"Abstract

 

Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABAA receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activated GABAA receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site."

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(I couldn't find a direct link to this article thru the BB search feature so I included it here)

 

I'm curious: does anyone have a direct link to scientific articles that contradicts the statement made several times in the article "Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site."?

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/

 

"Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?"

 

"Abstract

 

Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABAA receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activated GABAA receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site."

.

.

(I couldn't find a direct link to this article thru the BB search feature so I included it here)

 

I'm curious: does anyone have a direct link to scientific articles that contradicts the statement made several times in the article "Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site."?

 

 

I read the whole thing for you.

 

You are misinterpreting the article.

 

Mostly, it's discussing the theories behind benzo dependence.

 

To answer your question: the theory is that the a1 subunit of the gaba receptor is the one that is most affected by benzos (and z-drugs), and the most likely to be downregulated. That happens to be the receptor that induces sleep. Benzos in general modulate all subunit types: a1, a2, 3, 4 and 5, respectively.

 

The article went into discussion other substances that do not trigger the a1, and that might only trigger a3 for example, or a5.

 

They found that tolerance does not seem to occur when specific subunits are modulated at the benzo site, but this has nothing to do with the benzo drugs.

 

That's all.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/

 

"Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?"

 

"Abstract

 

Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABAA receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activated GABAA receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site."

.

.

(I couldn't find a direct link to this article thru the BB search feature so I included it here)

 

I'm curious: does anyone have a direct link to scientific articles that contradicts the statement made several times in the article "Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site."?

 

 

I read the whole thing for you.

 

You are misinterpreting the article.

 

Mostly, it's discussing the theories behind benzo dependence.

 

To answer your question: the theory is that the a1 subunit of the gaba receptor is the one that is most affected by benzos (and z-drugs), and the most likely to be downregulated. That happens to be the receptor that induces sleep. Benzos in general modulate all subunit types: a1, a2, 3, 4 and 5, respectively.

 

The article went into discussion other substances that do not trigger the a1, and that might only trigger a3 for example, or a5.

 

They found that tolerance does not seem to occur when specific subunits are modulated at the benzo site, but this has nothing to do with the benzo drugs.

 

That's all.

 

The article is well documented and imo does a good job of explaining the various theories of how benzodiazepines may affect the subunits of GABA receptors which often results in tolerance eg. hypnotic, sedative, depressant, etc. to the medications; except as clearly stated several times in the article: "there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/

 

"Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABAA Receptor Modulators?"

 

"Abstract

 

Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABAA receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activated GABAA receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site."

.

.

(I couldn't find a direct link to this article thru the BB search feature so I included it here)

 

I'm curious: does anyone have a direct link to scientific articles that contradicts the statement made several times in the article "Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site."?

 

 

I read the whole thing for you.

 

You are misinterpreting the article.

 

Mostly, it's discussing the theories behind benzo dependence.

 

To answer your question: the theory is that the a1 subunit of the gaba receptor is the one that is most affected by benzos (and z-drugs), and the most likely to be downregulated. That happens to be the receptor that induces sleep. Benzos in general modulate all subunit types: a1, a2, 3, 4 and 5, respectively.

 

The article went into discussion other substances that do not trigger the a1, and that might only trigger a3 for example, or a5.

 

They found that tolerance does not seem to occur when specific subunits are modulated at the benzo site, but this has nothing to do with the benzo drugs.

 

That's all.

 

The article is well documented and imo does a good job of explaining the various theories of how benzodiazepines may affect the subunits of GABA receptors which often results in tolerance eg. hypnotic, sedative, depressant, etc. to the medications; except as clearly stated several times in the article: "there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site."

 

I'll let Marigold1 fill in

FI Addendum asked:

I'm curious: does anyone have a direct link to scientific articles that contradicts the statement made several times in the article "Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site."?

 

 

No, because you can't.

This is all still hypothetic.

 

Here is an article from 2021. It is reviewing the article you linked (and other articles, studies..).

It is not contradicting the statement - but it is making clear that there need to be more research to verify the theories:

 

"Together, these features could result in variable GABAAR turnover rate in different neuronal populations and may explain why benzodiazepine tolerance for the sedative-hypnotic effects occur more rapidly in comparison to the anticonvulsant/anxiolytic actions (Bateson, 2002; Vinkers and Olivier, 2012), but this supposition requires further clarification."

 

It is a good sentence, because both Bateson, as Winkers + Olivier, supposed something, but yet evidence has not been found. The author Bateson, as well as the 2 writers of the article you posted, also only took old studies, and compared them to new theories. Thats a normal process, but it is a report about what is assumed and later they would add, hopefully, what has been verified. Thats how it works, nothing wrong about it.

 

Here is the link to the article (which explains the hole research and hopes around the receptors a bit better, too):

https://www.frontiersin.org/articles/10.3389/fnins.2020.616298/full

 

 

Thats my answer to FI Addendums question.

 

No one out there yet has found the answers to the questions:

- what exactly causes tolerance

- how can we create a med that does not cause tolerance

 

..and the subtypes of GABA receptors are just .. subtypes.

Imagine the grey hair scientists will get discovering the world of transmembrane GABAAR accessory proteins and the field of ligand-bound GABAARs.

 

 

In the end, they always take poor rats, fill them up with benzos or other meds, look at them and then kill them and take out their brains, and then take samples of the hippocampal GABAα receptors and check out the subunits found and the protein levels.

 

But this just means "the cells do look different than before" or "the protein levels changed". And then these findings are linked to a hypothesis and so on.

 

Still, you do not know if thats the only part in the body in the chain that causes tolerance/damage...  and still, you need a lot of studies to find out if cells of numerous individuals show the same changes and if the individuals did show the same behavior the extraction. Cause most of the time, before the brain cells are extracted, the animals are tested on memory, or - pain level they show (tolerance = agony).

 

:'(

 

 

Thank you Marigold1 for the time and effort you put in to provide the article, I very much appreciate that.

Thank you Marigold1 for the time and effort you put in to provide the article, I very much appreciate that.

 

You are welcome.

 

I have my problems with the term "tolerance". They normally work with 2 types of tolerance in these articles.

The first form of tolerance is called pharmcokinetic tolerance.

Pharmacokinetics has a look on how your body stores the drug in the blood plasma and tissues and how it is excreted again.

The second form of tolerance is called pharmacodynamic tolerance. It occurs when the receptor through which the drug acts is downregulated, making it less sensitive. Pharmacodynamic tolerance is pronounced when taking  benzodiazepines, they say.

 

The difference between the 2 forms of tolerance is, that pharmacokinetics deals with how a drug reaches its desired target site, while pharmacodynamics describes the effect at the target site.

It is important to understand the difference.

 

But I say, when I have a slow detox enzyme family P450, the efficiency / potency of the benzo is much higher for me than for a different person. Because my body needs more time to excrete the medication and therefore builds up a higher level, I would need less of the "average, normal" amount of the benzo. How could this contribute to tolerance, withdrawal and how would it affect the receptor. Or, on the other hand, if you got a patient with an extremely fast P450, it would mean you need a way higher dosage to get an effect. - would this mean the receptor develops a tolerance faster .. or not. I am not sure if this fits into the definition they use when it comes to Pharmacokinetics..

 

 

The future will be meds which are made only for you as a patient, based on your genetic code, current health situation of the hole body. Like in the science fiction movies. But until we reach this future I assume we will just continue to play trial and error.

 

 

Thank you Marigold1 for the time and effort you put in to provide the article, I very much appreciate that.

 

I find it interesting that you did not understand my simple, but down to the point reply. Yet you seem to have fully understood the 4 pages of information Marigold1 posted, which rival the original study itself.