Posted by MnemonicLife in 2015 re: GABAA a4 subunit protracted. Thoughts?

Also, if one was using methamphetamine and benzos would they be "double screwed?"

"I felt this paper was particularly germane here. The changes in GABAA subunit composition seem to be an undeniable result of the body attempting to counteract protracted BZD administration. Most notable is the increase in GABAA receptors containing the a4 subunit. These receptors are deemed "diazepam insensitive" and typical benzodiazepines have no affinity for them. The paper below looks at chronic Methamphetamine use and discontinuation in rats. GABAA receptors with the a4 subunit are found to up-regulate with the prolonged use of a number of drugs during both the period of abuse of the drug and after discontinuation of the drug. This is the case with the use of Ethanol, BenzOHs, Neurosteroids (perhaps both endogenous and exogenous ligands), and Methamphetamine.

In the study below rats administered Methamphetamine for 3-5 weeks showed an up-regulation of receptors with the a4 subunit while Meth was still being administered and during discontinuation. In fact, the GABAA(a4) receptors were found in densities 3x as much compared to rats in the control group for a median of 6 weeks after Meth use was discontinued. This finding is a huge revelation particularly since the rats were only administered Meth for 3-5 weeks!! If this finding pertains to BZD discontinuation as well, which I believe it does, is a fantastic demonstration that changes in GABAA subunit composition after the cessation of the causative agent do not necessarily correct themselves promptly and in this case the duration is quite shocking,.

As expected, the GABAA(a4) subunits that began to up-regulate during the continued use of Methamphetamine produced anti-anxiety effects in the rats when activated by the endogenous Neurosteroid "3α,5β-THP." 3α,5β-THP is synthesized in the human body when progesterone reacts with 5-alpha reductase I enzyme (5-AR1) and subsequently with 3-alpha-hydroxysteroid dehydrogenase (3a-HSD). There are several Neurosteroids in the CNS that are synthesized in this manner including Allopregnanolone (ALLO) along with 3α,5β-THP. All of the neurosteroids synthesized in this manner are potent positive allosteric modulators at nearly all GABAA receptors. They bind to a site different than those of benzodiazepines and can both augment the binding of GABA to the GABAA receptors (like Benzos do) and in higher concentrations can potentiate GABAergic currents at the receptor without GABA even present. Therefore, they are endogenous ligands to nearly all GABAA receptors that produce anti-anxiety, analgesic, and anti-depressant effects. GABAA receptors with a4 subunits are particularly sensitive to these neurosteroids.

However, when the Methamphetamine was discontinued in these rats, 3α,5β-THP affinity for GABAA(a4) receptors caused anxiety! This is the complete opposite effect that 3α,5β-THP is supposed to produce when binding to GABAA! Therefore, there is an abundance of these receptors with the a4 subunits and an endogenous ligand in the CNS that is supposed to attenuate anxiety thar actually exacerbates anxiety at these very receptors.

I think this finding is pretty amazing. It is a total reversal of what we expect to happen and can lead to malfunctioning of the GABAA receptors only after the Methamphetamine use was halted for a substantial period of time. If the results of this study carry over to the use of alcohol and benzodiazepines in humans, which there is strong reason to support, the up-regulation of these benzodiazepine insensitive GABAA receptors could remain in the CNS long after the use of Benzos! Moreover, the aberrant behavior of the endogenous Neurosteroid 3α,5β-THP acting inversely at these receptors, that is instead of producing anxiolytic effects (reducing anxiety) we see anxiogenic effects (creating anxiety), can cause substantial long term malfunctioning of the GABAergjc system for periods much greater than I though following Benzo discontinuation.

This strikes me as a very good hypothesis to explain the chronic under functioning of the GABAA receptors after BZD cessation for a protracted period.

What can be done about such a quagmire if these results can be demonstrated in humans and with BZD discontinuation syndrome as opposed to Methamphetamine discontinuation syndrome? According to the authors of the paper it's Flumazenil to the rescue The atypical arrangement of GABAA receptors with a4 subunits creates insensitivity to most benzodiazepines but modest affinity for Flumazenil which acts as partial agonist here. Typically Flumazenil acts as a neutral antagonist or weak partial agonist at most other GABAA receptors.

From the study it would seem the ideal time to administer Flumazenil would be prior to the discontinuation of the drug. As a partial agonist with modest affinity for GABAA receptors with a4 subunits, the authors concluded that Flumazenil can prevent the up-regulation of GABAA(a4) receptors caused by chronic drug use. However, Flumazenil use after discontinuation of the causative agent would most likely be of benefit by potentiating GABAergic currents by working as a partial agonist at receptors with a4 subunits. Nonetheless, one is made to believe that the potentiation of currents at these receptors by Flumazenil would be challenged by the inverse effects of  3α,5β-THP at the same receptors.

Thanks for reading. I know it is a rather long and dry post but I think it may hold some merit so any thoughts are welcome of course.

Neuroscience

19 December 2013, Vol.254:452–475,

A stress steroid triggers anxiety via increased expression of α4βδ GABAA receptors in methamphetamine dependence

H. ShenA. MohammadJ. RamroopS.S. Smith

HIGHLIGHTS:

Methamphetamine increases hippocampal expression of α4βδ GABAA receptors.

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The stress steroid THP reduces GABAergic current during methamphetamine withdrawal.

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THP’s effect was mediated by polarity-dependent effects at α4βδ GABAA receptors.

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THP paradoxically increases anxiety during methamphetamine withdrawal.

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This effect was prevented by flumazenil and α4 knock-out.

http://www.sciencedirect.com/science/article/pii/S0306452213007215?via%3Dihub  "

TG, this is a good find and an interesting paper.  One would hope that we could eventually get enough people to be fMRI or PET scanned to be able to see which exact subunits of the GABAA receptor are effected.  I think this would go a long way towards finding something to reverse it. 

Personally, I had flumazenil treatment and experienced no long term benefits from it.  Though I was off the medication for over a year when I received it.