Activation of α4β2δ GABAa receptor by finasteride?

[warbler]

As we all know:

http://www.propeciahelp.com/forum/viewtopic.php?f=13&t=7

propecia:

blocks Progesterone --> Allopregnanolone conversion, thus interfering with GABA-A receptor function in the brain (anxiety, possible seizures, depression)

I think I may have found why this occurs. First off, I am a full-time college student suffering from acute symptoms of “brain fog”, ED, etc…from propecia and as such I simply don’t have the time to go through, or the ability to remember everything here so I apoligize if anything I propose has already been stated somewhere on this forum.

http://www.allopregnanolone.com/

During adolescence, mice have the usual receptors, but also extra-high levels of a second kind that brings an anxious, rather than calming, response when THP attaches to it.

“The parallel with humans is that in humans there are similar hormonal changes going on in puberty,” Smith said.

(THP is allopregnanolone)

More scientific account of a similar study:
http://stke.sciencemag.org/cgi/content/abstract/2007/380/tw110

Shen et al. found that the neurosteroid known as THP (3α-OH-5α[β]-pregnan-20-one) decreased, rather than increased, chloride conductance through a specific GABA receptor composed of 42 subunits when this receptor was expressed in human embryonic kidney (HEK) 293 cells. In female mice, the abundance of the α4β2δ subunits, which were determined as critical for this reversed effect of THP, increased at the onset of puberty, whereas these subunits were barely detectable in prepubertal and adult animals. Electrophysiological recordings of hippocampal slices of pubertal mice confirmed that THP reduced GABA-mediated tonic inhibitory current and increased neuronal excitability, which is consistent with these GABA receptors serving as extrasynaptic tonic inhibitors of neural activity.

In adult animals, withdrawal of THP stimulates the appearance of α4β2δ subunits

(In case you missed it at the bottom: M. M. McCarthy, GABA receptors make teens resistant to input. Nat. Neurosci)

So these subunits are far less prevalent in adults and prepubertal animals however removing THP can cause the subunits to become more prevalent! The effect on adults versus adolescents on these receptors is opposite but I think I know why…

More details on the α4β2δ GABA receptor:
http://www.ncbi.nlm.nih.gov/pubmed/19523771

This polarity-dependent inhibition of alpha4beta2delta GABAR resulted from an increase in the rate and extent of rapid desensitization of the receptor, recorded from recombinant receptors expressed in HEK-293 cells with whole cell voltage clamp techniques. This inhibitory effect of 3alpha,5[alpha]beta-THP was not observed at other receptor subtypes, suggesting it was selective for alpha4beta2delta GABAR. Furthermore, it was prevented by a selective mutation of basic residue arginine 353 in the intracellular loop of the receptor,…

and finally:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1858651/

Please read this one. I may or may not be able to comprehend everything going on here but I just dont have the time (test tomorrow) to read and understand it right now. It is far longer and more detailed than any of the others and I could have easily missed something important in the meat of the article.

fluctuating levels of THP can increase expression of α4 and δ subunits

These receptors are normally expressed at very low levels, but at puberty, their expression was increased in CA1 hippocampus where they generated outward currents. THP also decreased outward current at recombinant α4β2δ receptors, an effect dependent on arginine 353 in the α4 subunit, a putative Cl− modulatory site

Main points I gathered from these studies:

Lack of THP stimulates the appearance of α4β2δ subunits in adults.

These subunits can have either a relaxing or an anxiety inducing effect depending on the presences of arginine in the alpha 4 subunit.

This polarity dependent inhibition resulted from an increase in the rate and extent of desensitization of the receptor (Leading to apathy, indifference?).

So finasteride blocks THP, which makes more α4β2δ subunits on our GABA receptors. When we dont have arginine these subunits can lead to anxiety, stress, and desensitization of receptors. This causes the brain to release more stress hormone, i’d imagine cortisol but I believe that may be inhibited as well, because THP is inhibited or maybe our body deals with the stress some other, unhealthier way. Then adrenal fatigue begins to come into play with our already off-balance hormones (maybe or maybe not until…).

Besides this, Finasteride also:…
Can lead to an accumulation of Progesterone

We stop taking finasteride and our accumulated progesterone, accumulated cortisol precursors if any, and testosterone and not inhibited in their respective conversions. Progesterone is now catalyzed to THP which then binds with α4β2δ in huge quantities causing massive stress and anxiety. The brain responds by releasing stress hormones like cortisol and more THP. The cortisol may work correctly but the added THP will counteract some, if not all of this effect. As a result, cortisol levels stay elevated for an extended period of time. Extended, elevated cortisol levels is the primary cause of adrenal fatigue.

Meanwhile, elsewhere in the body we are dealing with the aftermath of DHT, estradiol, testosterone imbalance. However, that is hardly the primary concern of a body that must first and foremost deal with the stress that is destroying it. Here is the link for what in my opinion is a great site for adrenal fatigue:

http://www.drlam.com/articles/adrenal_fatigue_related_conditions.asp
As you can see, normal cortisol levels arent necessarily an indicator of adrenal health but could simply mean more advanced levels of fatigue.

Honestly, the only thing I cared about when I crashed was my sexual health. I dont know how many sleepless nights I have had stressing about why I wasnt able to maintain an erection or why it didnt feel like it used to. By doing so I might have been only making my issues worse.

A few things more things I would like to point out:
I have taken NO2 supplements (arginine) from GNC at various points in my life for various reasons. When I first started feeling funny on finasteride I read that NO might be inhibited by the lack of DHT so I tried it. It didnt work like it used to as far as pumping me up, but it reduced my stress, made learning easier, and just made me more aware and happy.

I first starting feeling really bad on finasteride after a night of drinking. Alcohol stimulates the production of GABA. When the extra GABA bound to the modified receptors in my system did that simply cause a massive desensitization of my hypersensitive receptors? I know that seemingly in an instant I went from myself, to just numb to the world. And I was STRESSED about that (It didnt help that finals were coming up in two weeks)!

Taking saw palmetto (inhibits both types of 5a-reductase) allows me some respite from brain fog symptoms when I really need it. It inhibits THP, perhaps thereby reducing stress and activating some GABA receptors. By the way, I just finished taking a supplement that includes saw palmetto and beta sitosterol for about a week and a half. Without it I probably would not have the mental ability and endurance to find all these articles, put the information together, and write about them.

A little bit more about adrenal fatigue. If you followed the link you will see the number two related health condition: muscoskeletal system breakdown. I know there are other mechanism for joint pain/popping/degeneration proposed on this site but I have noticed the other symptoms there as well. Not to mention the other categories of symptoms.

Finally, I’m not familiar with everything that goes on in the brain during sexual intercourse and release. But if sexual activity releases ANY compound that binds to GABA receptors then it could lead to receptor desensitization. Personally, I was a stressed out little teenager. It took me years after high school to manage stress and become a well-adjusted individual (I’m 26 now and not so well-adjusted as I was then of course). Only then did I start to fulfill whatever sexual potential I had. Could it be possible that while we were on finasteride our brains began to associate sexual release with stress? Does anyone else feel numb mentally or stressed after orgasm? I fall asleep faster and deeper when I DONT have sex. As a matter of fact, the last time I did I couldnt sleep at all due to putting huge effort into trying to maintain an erection and lasting longer than a minute! I also understand and abide by the use it or lose it mentality when it comes to sexual function so it seems I may have a conundrum.

Let me know what you all think. Especially if someone can point out some obvious flaw or extract more information from the studies I posted. I would greatly appreciate any other pertinent information and analysis. I have been attacking this with all the vigor and determination I could muster since I crashed about 6 months ago. In hindsight, maybe I should have been more deliberate and allowed my body to recover at its own pace.

Again, the amino acid that inhibits the outward current that appearently causes stress and desensitizes the GABA receptor is arginine. Found in NO supplements.

[Mew]

Please fill out the following so we can get a better sense of your history and issues from the drug:

viewtopic.php?f=3&t=371

As well it would be appreciated if you could fill in the missing info on your profile (drug, dates taken, etc).

[warbler]

After having the time to fully read and understand these documents I realize that I came to some erroneous conclusions before:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1858651/

Arginine does allow THP to inhibit the outward current of the alpha 4 subunit. But I incorrectly stated that this outward current is what causes stress when in fact, inhibition of the outward current is what causes anxiety.
Only when a basic residue such as arginine is bound to site 353 of the GABA receptor is this inhibition observed. A neutral residue does not allow THP to inhibit the current.
Also, I missed something I believe could be very important which I colored below.

Everything else I still believe is valid. Including:

fluctuating levels of THP can increase expression of α4β2δ subunits

I said before that maybe this fin-induced lack of THP put so much stress on our adrenals that they reached their breaking point. Plausible to me, and I still think that could be part of the problem. But why does the brain modify itself to produce stress during puberty in the first place?
from the same study:

Stress is also associated with activation of the hypothalamo-pituitary-adrenal axis.

These studies are from endo.endojournals.org:
http://endo.endojournals.org/cgi/content/full/146/1/137
http://endo.endojournals.org/cgi/content/full/149/7/3581
http://endo.endojournals.org/cgi/content/full/145/1/59

They describe, in order posted:

1. Gender differences in stress-induced HPTA activation
2. Something about limbic vasopressin (look down in hypothalamus part) and the role of androgen receptors in organizing HPTA
3. Quite frankly, from looking at the title, I have no idea what this one is talking about yet. Came up when I searched stress and HPTA though

From the first endo study (abstract):

Puberty-related shifts in parvocellular neurosecretory function in males are emphasized by stress-induced shifts in neuronal activation

Parvocellular neurosecretory cells are neurons of the paraventricular nucleus in the hypothalamus (wiki). They exert direct control over a variety of body functions including appetite and automatic functions of the brain stem and spinal cord.
Most important to us, some directly project on the pituitary where they release oxytocin or vasopressin.
http://en.wikipedia.org/wiki/Pituitary

From same study (5th paragraph of discussion):

the brunt of the pubertal alterations in males in HPA function appear to rely on changes in stress-induced neuronal activation rather than steady-state alterations in peptide expression

Apparently, stress plays a major role in the brain modifying itself to alter HPTA function.
I havent had the time to read these studies thoroughly yet and I dont want to post any (more) false information but I think I might be on to something.

Working hypothesis at the moment:

• We know finasteride inhibits THP (allopregnanolone) production.
• Studies I posted here state α4β2δ subunit expression increases in adults when THP is absent.
• These subunits are a (the?) mechanism the brain uses to create stress during puberty.
• Stress allows the brain to permanently alter its regulation of the HPTA during puberty and perhaps on fin.