27 replies to this topic

[brotherx]

Hi,

I just found the following abstract - I thought it might could also be interesting for you!

Best regards

Alex


Titre du document / Document title
Chronic selegline administratioln transiently decreases tyrosine hydroxylase activity and mRNA in the rat nigrostriatal pathway

Selegiline, a selective monoamine oxidase type B inhibitor, is beneficial in the treatment of Parkinson's disease. However, this beneficial effect is only transient, and patients must ultimately resort to treatment with standard levodopa therapy. We studied the effects of chronic selegiline treatment on the rat nigrostriatal pathway, to elucidate a neurochemical correlate for this adaptive clinical response. Selegiline treatment for 3, 7, 14, or 21 days decreased tyrosine hydroxylase (the enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis) activity in the cell body regions (substantia nigra) of the nigrostriatal pathway


Auteur(s) / Author(s)
VRANA S. L. (1) ; AZZARO A. J. ; VRANA K. E. ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) West Virginia univ. health sci. cent., dep. neurology, Morgantown WV 26506, ETATS-UNIS
Résumé / Abstract


Revue / Journal Title
Molecular pharmacology (Mol. pharmacol.) ISSN 0026-895X CODEN MOPMA3
Source / Source
1992, vol. 41, no5, pp. 839-844 (48 ref.)

[FunkOdyssey]

That is interesting. Homeostasis strikes again...

[brotherx]

Hi,

yes - this was also my first thought!
Enjoy your weekend!

Alex

"Homeostasis = any self-regulating process by which biological systems tend to maintain stability while adjusting to conditions that are optimal for survival. If homeostasis is successful, life continues; if unsuccessful, disaster or death ensues. The stability attained is actually a dynamic equilibrium, in which continuous change occurs yet relatively uniform conditions…"

That is interesting. Homeostasis strikes again...

[Lufega]

*Bump

It's an old thread but oh so relevant right now. Finally found a study that confirms what I'm going through right now. Selegiline totally messed me up. I am running with very little dopamine activity. Currently have depression, no motivation, fatigue, increased social anxiety. Basically, everything I was trying to undue with selegiline. How long does it take for the down-regulation to reverse???

[bgwithadd]

I don't think homeostasis ever counters soemthing 100%. You can see this more as a marker of the benefit that deprenyl brings.

This is just why peopel cycle drugs, not a reaosn to ditch them, really.

Edited by bgwithadd, 25 February 2009 - 05:03 AM.

[Cuil]

Yea, I figured this would happen. Doesn't suprise me at all. I went crazy when I ran out of selegelline over the summer. I felt apathy and depression the most. Also, no physical energy.

[FunkOdyssey]

Yeah selegiline shows its ugly side when you stop taking it. The only substance I've seen documented to increase tyrosine hydroxylase activity is nicotine, however this is either unhealthy or impractical for most people so waiting things out is probably your best option.

[lynx]

Nicotine patch is an option.

[FunkOdyssey]

Thats true, I wasn't going to mention it because of the negative stigma but that would work. You'd want to start very low as a non-smoker, 1/16th of a 21mg patch made me light-headed and turned out to be excessive. I am using memantine and lithium orotate though, both of which may increase sensitivity.

[ajnast4r]

Yeah selegiline shows its ugly side when you stop taking it. The only substance I've seen documented to increase tyrosine hydroxylase activity is nicotine, however this is either unhealthy or impractical for most people so waiting things out is probably your best option.

vitamin D effects tyrosine hydroxylase as well

http://www.ncbi.nlm..../pubmed/9011759

Vitamin D increases expression of the tyrosine hydroxylase gene in adrenal medullary cells.
Puchacz E, Stumpf WE, Stachowiak EK, Stachowiak MK.

Laboratory of Molecular Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA.

We examined expression of the 1,25-dihydroxyvitamin D3 [1,25-(OH)2 D3] receptors in chromaffin cells of the adrenal medulla and the effects of 1,25(OH)2 D3 on expression of the tyrosine hydroxylase (TH) gene. Accumulation of 1,25(OH)2 D3 in the nuclei of adrenal medullary cells, but not in the adrenal cortex, was observed in mice intravenously injected with radioactively labeled hormone. 1,25(OH)2 D3 produced concentration-dependent increases in the TH mRNA levels in cultured bovine adrenal medullary cells (BAMC). The maximal increases (2-3-fold) occurred at 10(-8) M 1,25(OH)2 D3. Combined treatment with 1,25(OH)2 D3 and 20 microM nicotine had no additive effect on TH mRNA levels suggesting that transsynaptic (nicotinic) and vitamin D (hormonal) stimulation of TH gene expression are mediated through converging mechanisms. Induction of TH mRNA by 1,25(OH)2 D3 was not affected by calcium antagonist TMB-8. By increasing expression of the rate limiting enzyme in the catecholamine biosynthetic pathway, 1,25-(OH)2 D3 may participate in the regulation of catecholamine production in adrenal chromaffin cells. This regulation provides mechanisms through which 1,25(OH)2 D3 may control response and adaptation to stress.

PMID: 9011759

www.vitamindcouncil.org/depression.shtml

[Lufega]

Activation of tyrosine hydroxylase mRNA translation by cAMP in midbrain dopaminergic neurons.
Chen X, Xu L, Radcliffe P, Sun B, Tank AW. Department of Pharmacology and Physiology, Box 711, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA.

During prolonged stress or chronic treatment with neurotoxins, robust compensatory mechanisms occur that maintain sufficient levels of catecholamine neurotransmitters in terminal regions. One of these mechanisms is the up-regulation of tyrosine hydroxylase (TH), the enzyme that controls catecholamine biosynthesis. In neurons of the periphery and locus coeruleus, this up-regulation is associated with an initial induction of TH mRNA. In contrast, this induction either does not occur or it is nominal in mesencephalic dopamine neurons. The reasons for this lack of compensatory TH mRNA induction remain obscure, because so little is known about the regulation of TH expression in these neurons. In this study, we test whether activation of the cAMP signaling pathway regulates TH gene expression in two rodent models of midbrain dopamine neurons, ventral midbrain organotypic slice cultures and MN9D cells. Our results demonstrate that elevation of cAMP leads to induction of TH protein and TH activity in both model systems; however, TH mRNA levels are not up-regulated by cAMP. The induction of TH protein is the result of a novel post-transcriptional mechanism that activates TH mRNA translation. This translational activation is mediated by sequences within the 3' untranslated region (UTR) of TH mRNA. Our results support a model in which cAMP induces or activates trans-factors that interact with the TH mRNA 3'UTR to increase TH protein synthesis. An understanding of this novel regulatory mechanism may help to explain the control of TH gene expression and consequently dopamine biosynthesis in midbrain neurons under different physiological and pathological conditions.

Would forskolin help???

[bgwithadd]

cAmp also shuts down the prefrontal cortex, though, according to other studies. It's probably basically homeostasis again - the extra dopamine made is due to the decreased functionality of the HCN channels.

Your dopamine is just going to balance to normal, though. More isn't really better and the levels are less important than what's being transported to the right areas, which is what deprenyl will improve.

[hullcrush]

Interesting. I must have yawned 100 times on 5 mg Selegiline, my friend probably thought he was really boring
I've never felt sleepy while driving before, it was scary.
On a side note, as a non-smoker, I took a 1/4 of a 21 mg nicotine patch a week ago. Yikes. I still have palpitations. So much acetylcholine, holy shit. My chess rating went up 100, but I'd rather sleep.

Edited by hullcrush, 25 March 2009 - 07:41 PM.

[Lufega]

cAmp also shuts down the prefrontal cortex, though, according to other studies. It's probably basically homeostasis again - the extra dopamine made is due to the decreased functionality of the HCN channels.

Your dopamine is just going to balance to normal, though. More isn't really better and the levels are less important than what's being transported to the right areas, which is what deprenyl will improve.

I don't think I follow. Social anxiety, lack of motivation, apathy, isolation and some forms of depression are all considered due to low dopamine activity, at least in the D2 receptors. In fact, these are essentially the negative symptoms of schizophrenia. I thought by taking deprenyl, I would bring up D2 activity to normal from it's current retarded low state but it had the complete opposite effect. ONLY the first day I used deprenyl did I feel a boost...it was downhill from there and my dose was never higher than 1 or 2 mg, minus the first day, 5 mg.

In short, deprenyl didn't improve anything but rather, worsened things. Mmmmm....or is this just a temporary, readjusting phase?

[bgwithadd]

Well, for starters, the dopamine hypothesis of [fill in the blank] is a dramatic oversimplification, and the more I read the more I believe it's probably just plain wrong. There's much more to the brain than a few neurotransmitters that have a certain level and you just top them off when you get low.

Simply upping dopamine does little or nothing for me when it comes to those things. Dopamine is a bit of a red herring, even a side effect when it comes to how stimulants work. When you look at adderall, it had a dramatic effect, but it does a lot more than increase dopamine.

First off, it is also a NE reuptake inhibitor in addition to a dopamine releaser, and the amounts of dopamine actually released are minute. It also changes dopamine transportation, forcing it into the receptors whether they want it or not. When stressed out, or when you have something wrong with your dopamine transport or your cAMP signalling pathways, your brain will build up cAMP in the prefrontal cortex. This blocks the cells off entirely and tells them to shut down. It basically says "I am too weak to go on! I need rest, guys!" and stops functioning until (or if) it thinks it has enough energy to go on. NE will change the HCN channels and signal them to open up. DAT will simply force them to work if they want to or not (which is also why amphetamines can be so neurotoxic, they literally can work your brain to death).

If it was just upping of dopamine that fixed attention, we'd all take l-dopa and have done with it. However, if you've done that, you'll know it doesn't help much. Maybe some, but not enough to make it worth the effort. Mostly, you just get lots of shitty (or sometimes good) side effects.

So, don't expect you are going to get anything simply due to upping dopamine. But, deprenyl does more than that. The biggest thing MAO-B inhibition does is increase your levels of phenylethylamine. This fuctions much like adderall does. Having taken both PEA and adderall, I'd say it's like taking adderall except it is much much more feelgood. However, the levels deprenyl ups are not as dramatic as taking deprenyl+PEA (which is unfortunately kind of dangerous), but you should still get some help in that regard.

You mentioned in another thread you were taking a bunch of tyrosine etc. You can't just take all that crap and then take deprenyl and not expect bad results. What happened is that you hit the catecholemine system from both ends, you were producing way more and then you took away the means to remove the excess. SO, the only thing the body can do is to stop making more, and you put it into panic mode and it probably basically stopped completely. You need to not make such dramatic changes in your chemistry or you will get problems.

By doing it the way you have, your dopamine is higher than normal, but you have killed off your NE production. MAO-B metabolizes dopamine but not NE, after all, but the production method is linked to both. That means to damp down the ridiculous amount of dopamine you are pumping into your brain, your brain also had to stop making NE. That's why you are in a tailspin right now. Your dopamine levels are fine.

Dopamine levels basically just are not an issue, anyway, I am coming to believe, for the reasons I stated above. It's not dopamine itself that causes these cognitive problems. If you really had low dopamine, you would have symptoms like hand tremors etc. because it does a lot more than regulate cognition. The problem with ADDlike symptoms seems to more likely be dopamine transport ie not getting where it's supposed to go (which could be due to low PEA, which all ADDers seem to share in common), low NE (which as I said opens up the prefrontal cortex cells), or simply low bloodflow to the areas of the brain like prefrontal cortex (again, which ADDers seem to have in common, according to MRIs). Plus of course, a tousand illnesses or deficiencies could be the root cause of any of this. But to simply say 'low dopamine' or 'high dopamine' to explain ADD or schizophrenia is a tremendous joke at this point. We are talking theory from the 40s that looks more and more full of holes with each passing year. However, this is what has been believed for decades and what you will hear from 99% of doctors even now.

[Lufega]

bgwithadd,

Thanks for the post. There's more I need to learn about it, specially how cAMP functions in the frontal cortex, etc. Can you point me to some literature? You mentioned hand tremors, I do have tremors on both hands that showed up when I was 18/19 at around the same time all these other problems showed up. I also have low blood pressure. There might be more to this than just dopamine but D is the at center stage here. Read about the mesocortical and mesolimbic tracts. There are basically dopaminergic tracts and they've been found to control motivation, sociability etc. It's late now but I'll try to post some links and studies tomorrow. When I was using a small amount of tyrosine, say, 500 mg, all my Sx were reduced, transiently mind you, say a 4-5 hours and I probably needed to re-dose. Maybe my D neurons aren't as defective to where I resemble a patient with parkinson's but my research led me to conclude that I will eventually get there.

I never tried L-dopa during this time but tyrosine was enough. Additionally, I was writing in a social anxiety forum and others with SAD, ADD etc., also showed good results from tyrosine. However, this isn't fixing anything, it's simply charging up the few neurons that remain intact to produce more D. My positive, albeit anecdotal, experience with tyrosine lead to me conclude dopamine (and NE) is the problem. We use dopamine in the emergency setting for hypotensive crisis, I'm dying to take a vial and inject it on myself. But I'm cautious.

You presented a new idea I hadn't thought of. I know that is Schizo, it's not high or low D, like you propose, but the actions of D1 and D2 are reversed. There's more D1 action and less D2 when it's normally the opposite. People with ADD seems to have half this effect where only the D2 are messed up and the D1 seems to be normal. This supports your idea very well and I'm starting to be a believer. It could also be a double take, low production and poor binding. How would this explain low NE and low BP? Then NE receptors or transport should also be impaired.

This needs further research...

[yoyo]

have you tried an nri?

[FunkOdyssey]

I'm going to be experimenting with pramipexole and I'll update with results when it arrives.

[OneScrewLoose]

I have ADD and I've been taking 5mg of Deprenyl for a while and it really helps.

If ADD were as simple as NE instead of dopamine then Strattera would actually work.

I seem to be different from most people that have ADD and have very high anxiety. Anything that adds NE for me screws me up it seems.

Beta blockers help with both anxiety and concentration for me.

[Lufega]

Beta blockers just block the effect of epinephrine on its receptors. Why are we adrenalin dominant? Is magnesium deficiency at the root of the cause? NE has preferential binding over Epi. but when NE is low, EPI. takes over. So low NE due to low Dopamine could also be a cause..

[Lufega]

I'm going to be experimenting with pramipexole and I'll update with results when it arrives.

Watch out for the cross-dressing side effects...

Seriously though, how's the memantine working for you? That also has D-agonist functions right?

Edited by Lufega, 27 March 2009 - 02:30 AM.

[FunkOdyssey]

Not really, there is one in vitro study that showed some D2 agonism but I don't think it translates to the real world. Memantine doesn't produce any of the effects or side effects typically associated with D2 agonism.

It seems to help with cognition and reduces brain fog, those are the main subjective benefits I can attribute to it. And of course, if I were using any stimulant medication (I'm not currently) I would expect it to prevent tolerance and synergize nicely. That's about all I expect from it. I do think the stimulant tolerance prevention may apply much more broadly than just the classic ADHD medications though.

[bgwithadd]

Onescrewloose - didn't I just say the brain isnt like a car batter low on acid? How'd you take that conclusion from what I said? It's probably dopamine transport that's broken in most ADDers. To take prop. for ADD is completely retarded, btw. Guanfacine is what you should take if you have high anxiety. It does a lot more than just reduce anxiety, but it's proven as effective as adderall for concentration. In fact it works by part of the same exact mechanism adderall does...triggered in a completely different manner. Since this mechanism has nothing to do with increasing dopamine (and no mechanism of how adderall works does either), maybe my words will start to make a little more sense to you. Also, anxiety can be a cognitive issue, but if that's the core issue then by definition, it's not ADD! It's GAD. Not that the diagnosis matters, except if that's what it is you should probably avoid stims.

Lufega - look for the studies on guanfacine for ADHD treatment. I believe that harvard med ran them and discovered its mechanism of action. If ou have trmors perhaps you do have low dopamine, but bear in mind that lithium can cause this effect as well. When was the original onset of your issues? Maybe we can get to the bottom of this once and for all if you just tell the whole story, or at least have a history to work with in case issues come up.

[Lufega]

Lufega - look for the studies on guanfacine for ADHD treatment. I believe that harvard med ran them and discovered its mechanism of action. If ou have trmors perhaps you do have low dopamine, but bear in mind that lithium can cause this effect as well. When was the original onset of your issues? Maybe we can get to the bottom of this once and for all if you just tell the whole story, or at least have a history to work with in case issues come up.

Thanks for taking interest. I only recently started lithium and I've only taken 3 5 mg pills so I don't think it's had any negative effects to this point. My tremors may be due to low dopamine --> low NE --> high epinephrine. Tremors in general seem to be caused by magnesium and B1 deficiency. I used high dose benfotiamine, fursultiamine and magnesium for one months and my tremors completely went away but It was very difficult to maintain this dose long term due to cost and scheduling. I thinkt he mechanism was by repairing peripheral and maybe central nerve damage since I do have an autonomic system problem. However, a few weeks after stopping, it take back. So whatever was damaging the nerves in the first place is still present. I also have other motor problems. For example, today the Doc was looking at the fundus of my eye and when I was intentionally trying to keep my head still, it produced a noticeable tremor. Weird. By the way, he found a weird venous-arterial anastomosis in my eye but he didn't want to comment further on that. I'll write my regimen and story and post it in a few. I'll look up guanfacine for ADHD.

[hullcrush]

Thanks for taking interest. I only recently started lithium and I've only taken 3 5 mg pills so I don't think it's had any negative effects to this point. My tremors may be due to low dopamine --> low NE --> high epinephrine. Tremors in general seem to be caused by magnesium and B1 deficiency. I used high dose benfotiamine, fursultiamine and magnesium for one months and my tremors completely went away but It was very difficult to maintain this dose long term due to cost and scheduling. I thinkt he mechanism was by repairing peripheral and maybe central nerve damage since I do have an autonomic system problem. However, a few weeks after stopping, it take back. So whatever was damaging the nerves in the first place is still present. I also have other motor problems. For example, today the Doc was looking at the fundus of my eye and when I was intentionally trying to keep my head still, it produced a noticeable tremor. Weird. By the way, he found a weird venous-arterial anastomosis in my eye but he didn't want to comment further on that. I'll write my regimen and story and post it in a few. I'll look up guanfacine for ADHD.

I had an isolated instance where I took atenolol and tyrosine on the same day. I'd suggest this highly before injecting dopamine, it's just really a peripheral pressor. I think you can extract why tyrosine and atenolol together would be a good idea. I took 2g of tyro and 50 mg of atenolol. My refractory period was reduced to about 5 minutes. Maybe a plasma catecholamine test is in order. The only real test that's came back out of range in me for about 50 things was norepinephrine elevation, and I abstain from pharmaceutics 5x their half-lives before I get blood tests (for those that follow regular kinetics).

Once the beta block wore off, I had some serious flashbacks (a common side effect of massive norepinephrine release, akin to yohimbine in PTSD patients causing flashbacks). This caused me to discontinue. Disulfiram would also inhibit dopamine hydroxylase.

[dumbdumb]

So, silly question probably, but just have to check -

What's the ideal way to handle homeostasis? Is cycling really the best option we've got? Does homeostasis beat the quest for engineered intellectual evolution? I know I've got to kick my stack up a notch - but I'm already down so low that I can't bring myself to start taking anything that might leave me even lower later.

[OneScrewLoose]

Can someone go into more depth of how low NE can cause a lot of adrenalin problems? Are the beta receptors agonized by both adrenalin and NE?

I took Nortriptyline, which increases NE, for a while and it helped, but gave me a wicked tremor in my hands.

How long does guanfacine work?

[bgwithadd]

dumbdumb - the best way is to not worry about it. It's not as serious of a problem as it seems at first glance. If your body just kept producing dopamine forever your heart would stop so it of course slows down production, but you will still have more than when you started. In most cases, but as I said dopamine and NE production are tied together so it's possible to make wacky situations where you have them out of balance like lufega seems to have done. That's why you don't take too many similar drugs without lots of care.

oneswcrewloose - You take guanfacine once a day. First off, there are alpha and beta receptors for adrenaline. You really don't want to use beta blocker just for the heck of it as it can kill you. Alpha blocker like guanfacine is much safer, but still can cause issues. For me I had to decrease dose.

As for low NE causing adrenaline problems, that is not usually the case. I think Lufega was trying to say low NE caused low blood pressure which caused low bloodflow which caused massive anxiety. I know this route is possible, because on too high a dose of guanfacine I got massive anxiety. But, for most people the opposite is true. That is a very rare side effect of guanfacine, and at a lower dose it causes me less anxiety.

So technically low NE could cause low BP and that could cause anxiety due to low bloodflow. However, that's unusual. The problem is, in the brain often too low and too high of the same thing has the same symptom. This is the case with confusion and acetylcholine, and with NE and cortisol in regards to blood pressure and anxiety. Too high of cortisol is blamed for many problems, but having too little is strongly linked to PTSD. So, perhaps cortisol is more a marker in most people, but if you have low cortisol and high NE you tend to have very accelerated learning, but the problem is there is negative learning as well as positive learning. So you learn negative behaviors IE you learn too well about social behavior to the point you barely want to leave the house.

If you have a lot of NE you are bound to have anxiety issues, nd in most people I believe this is more likely. However, many ADD folk have low NE, and NE plays a big role in transporting dopamine (if it doesn't get transported to prefrontal cortex, it's useless, which is probably why ritalin doesn't do crap for many people with ADD). As I said before, ADD and anxiety and depression can all three have the same symptoms, and all of them can cause the other. And of course, there's all the other stuff that could cause any of the three issues like lyme's blah blah blah. The key is to see what meds work for you and try to figure out your route problems and try to learn all you can if you are having issues figuring out what's going on.

I guess the pop. is a commonly prescribed med for anxiety, but I would be leery of it, especially being young. I'd almost forget everything your doctors have told you (if anything) and try to find out for yourself what the best meds are. Guanfacine not only calms your nerves but has a strong effect on actual cognition by signalling the prefrontal cortex cells to wake up and accept dopamine, in the same way that NE and amphetamine do. In ten years, guanfacine (in a new patented formula) will be the most proscribed ADD drug. The off patent stuff that does not last as long for the cognitive part (halflife 3-4 hours I think) costs five bucks a bottle at costco. The new will probably be 130 per bottle.

As an aside, a lot of the medicines prescribed for high BP are actually very dangerous and have little backing as to actually improving health because many of them actually increase pulse pressure, which is how hard each heart beat hits you. But they are on patent so marketed like crazy.

So the moral is (and coming here is a good start) research all you can and see what's best for you. Unfortunately anxiety is tough to treat but many supps do help to varying degress. Some help with ADD as well, but they all either last a short time or are very far from a whole cure or have some other drawback (like the PEA deprenyl combo, which is unfortunately very dangerous because it's hard to dose just right).