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The search for a safe Alpha7 Nicotnic Receptor Agonist?


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#31 NR2(x)

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Posted 09 September 2010 - 07:32 AM

You are correct about your understanding of reversiable inhibitors. Although I would add that an equilibrium will establish where by amount X is Bound and amount Y is free, with individual molecules switching rapidly between the two.
Irreversiable inhibitors often form covalent bonds with the enzyme substrate or modify/ break the enzyme. These enzymes are uneffect until they are destroyed

#32 aLurker

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Posted 09 September 2010 - 09:25 AM

Therefore, there could be very slight build-up going by half-lives and possibly a bit more as there may be some residual acetylcholinesterase inhibition after the half-lives are done and over with.

I don't have time to post any good research tonight, but I wanted to mention something about this point. In one of my last posts I asked about the resynthesis rate of AChE after inhibition...which was a pretty big brain fart, as galantamine (and all other AChEIs we discuss here, I believe) is a reversible inhibitor. (Which is a good thing, as resynthesis period is measured in weeks). From a review I read about Hup A, I think this means the molecule attaches directly to AChE, and prevents it from binding to ACh, and detaches when it naturally leaves the brain/body—returning the enzyme to normal functioning at that point. So, what I think this means is that there wouldn't be any residual inhibition after clearance of the drug from the brain. This is a small but potentially critical point in trying to figure out if any kind of increased steady state level is reached wrt AChEI effect.

Do you guys agree with this, or is one of these assumptions incorrect?

Will still be examining the research closely to try to get more specific answers about the levels, but in looking just now, there are about 350 papers on AChE inhibition to look through, so it's probably going to be a somewhat involved project.

Galantamine and nicotine: This seems like the very definition of synergy...the allosteric potentiation effectively means that the same amount of agonist (nicotine) will have a greater effect at the receptor, and (possibly?) without the downregulation that would come with the greater amount of agonist needed to achieve this effect without the allostery.

I'm also curious what concerns yowza had about the combination. In reading about the allosteric modulation, I seem to recall mention that direct agonism of nAChRs, perhaps at certain levels, had a potentially undesirable effect. Regardless, cycling is still probably a good idea, as nicotine is subject to tolerance at nAChR and downstream dopamine, and as Mr. Barleycorn mentions, galantamine's downstream effect on dopamine is almost certainly going to cause downregulation, even if its PAM does not. I also thought someone raised the possibility of rebound upregulation of AChE levels with on-off galantamine dosing, but I can't seem to find it just now. If so, it might make sense to use galantamine in longer cycles, and nicotine either short-period or as-needed.


There seem to be different types of reversible inhibitors. Galantamine is a reversible, competitive inhibitor of acetylcholinesterase. The wiki on competitive inhibition says the following:

Any given competitive inhibitor concentration can be overcome by increasing the substrate concentration in which case the substrate will outcompete the inhibitor in binding to the enzyme.


I think I mentioned the part about the possibility of rebound upregulation of AChE levels with on-off galantamine dosing. This is unfounded speculation on my part and merely a possibility my excessive worrying thought we should take into account. Whether or not our bodies tries to outcompete the inhibitor by increasing the concentration or AChE is obviously something which requires a reputable source (and wiki doesn't count).

And yeah, alpha 7 receptors are upregulated by nicotine.

Downstream downregulation of dopamine at least sounds like it could be a problem though, would this somehow be alleviated by skipping the nicotine patch while you sleep or is this wishful thinking on my part? This might also be a problem for norepinephrine (I'm mentioning this because this is probably a part of the motivational effects chrono and me are after here). Though the regulation of neurotransmitters during chronic nicotine shows at least some evidence to be dependent upon brain regions at least in rats.

And finally, instead of looking through 350 papers on AChE inhibition perhaps it would be wise to first investigate if this is an issue with galantamine or if it is possible to find a dose below the threshold for AChE inhibition.
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#33 medievil

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Posted 09 September 2010 - 09:14 PM

Nicotine also binds to (α4)2(β2)3 and (α3)2(β4)3 in the brain, is there any data wheter it also upregulates those?

Long term nicotine use does cause simular changes to dopamine as weve seen with other drugs of abuse,

Am J Psychiatry. 2008 Apr;165(4):507-14. Epub 2008 Mar 3.
Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse.
Fehr C, Yakushev I, Hohmann N, Buchholz HG, Landvogt C, Deckers H, Eberhardt A, Kläger M, Smolka MN, Scheurich A, Dielentheis T, Schmidt LG, Rösch F, Bartenstein P, Gründer G, Schreckenberger M.

Department of Psychiatry, University of Mainz, Untere Zahlbacher Strasse 8, 55131 Mainz, Germany. fehrc@uni-mainz.de
OBJECTIVE: All drugs of abuse induce a phasic dopamine release within the striatum that does not undergo habituation. Prolonged substance consumption impairs the natural function of the mesolimbic dopamine system, as shown by a decrease in the availability of striatal dopamine 2 (D(2)) receptors in patients suffering from cocaine, heroin, amphetamine, and alcohol dependence. However, it is unclear whether similar changes can also be observed in heavy-smoking nicotine-dependent smokers. METHOD: In vivo D(2)/D(3) receptor availability was determined with [ (1F]fallypride positron emission tomography in 17 heavy-smoking nicotine-dependent subjects and in 21 age-matched never-smoking comparison subjects. The smokers were scanned twice: first, during a period of usual consumption and second, 24 hours after smoking cessation. RESULTS: Independent of the withdrawal status, the nicotine-dependent smokers displayed significantly less availability of D(2)/D(3) receptors within the bilateral putamen functionally covering parts of the dorsal striatum, as compared to the never-smoking subjects. Nicotine craving under the consumption condition correlated positively with D(2)/D(3) receptor availability within the ventral striatum but negatively with D(2)/D(3) receptor availability within the anterior cingulate and inferior temporal cortex. CONCLUSIONS: Similar to other types of substance abuse, nicotine dependence is associated with low availability of dorsal striatal D(2)/D(3) receptors. In contrast to previous findings on abstinent alcohol-dependent patients, nicotine craving seems to be maintained by a region-specific shift in D(2)/D(3) receptor availabilities, with higher availability within the ventral striatum but lower availability within the anterior cingulate and inferior temporal cortex.


There's some very interesting info here, good work guys, still have to read the whole thread, wich i'm gonna do now.

Edited by medievil, 09 September 2010 - 09:14 PM.

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#34 medievil

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Posted 09 September 2010 - 11:52 PM

Downstream downregulation of dopamine at least sounds like it could be a problem though, would this somehow be alleviated by skipping the nicotine patch while you sleep or is this wishful thinking on my part?

That most likely wont work, in fact it could disrupt your sleep pattern, wich is i the reason you need to wear the patch also while asleep and not take it off before bedtime. (as far as i'm aware).

From my own experience tolerance develops fairly rapidly to the effects of nicotine and after a while it actually started to make me pretty irritable. As most people may know i'm a big proponent of memantine and a beleiver in its tolerance reducing propertie's, i know of 2 people confirming that memantine does in fact work against nicotine tolerance and my own first impression seems to confirm that, i say impression as ive only been using the patch for 2 weeks now and its too early to say, but it does seem to maintain the positive effects.

I also used to be addicted to the nicotine patch, after i ran out i started craving nicotine so badly i was searching all over the house for some leftover patches (i was out of money that time and patches are expensive so couldnt buy any at the pharmacy), i was thinking of just going for a pack of sigarettes instead but i didnt end up doing that, after 2 days the craving was allmost gone but stayed there for a bit untill i was on 20mg of memantine wich COMPLETELY reversed my cravings for nicotine, and i actually wasnt really too interested, but 2 weeks ago i just decided why not, and buyed another pack of patches.

There is some research showing that NMDA antagonists slow nicotine tolerance:
(PMID: ) The NMDA antagonist dizocilpine (MK-801) attenuates tolerance to nicotine in rats
These results suggest that the NMDA receptor may be involved in adaptation to both unconditioned and conditioned behavioural responses to nicotine.

(PMID: 18452252) The role of NMDA receptor antagonists in nicotine tolerance, sensitization, and physical dependence: a preclinical review
The aim of the present review is to discuss preclinical findings concerning the role of N-methyl-D-aspartate (NMDA) receptor neurotransmission in mediating the behavioral effects of nicotine, tolerance, sensitization, dependence, and withdrawal. Based on preclinical findings, it is hypothesized that NMDA receptors mediate the common adaptive processes that are involved in the development, maintenance, and expression of nicotine addiction. Modulation of glutamatergic neurotransmission with NMDA receptor antagonists may prove to be useful in alleviating the symptoms of nicotine abstinence and facilitate tobacco-smoking cessation.

(PMID: B8032593) Behavioural and neurochemical adaptations to nicotine in rats: influence of NMDA antagonists
The results suggest the involvement of NMDA receptors in adaptations of the behavioural and neurochemical effects of nicotine that occur as a result of repeated administration of the drug.

Wich togheter with those 2 experiences ive got make it look promosing.

One thing tough, memantine is a alpha7 antagonist and pretty much the opposite of what this thread is about, altough it has been said that A7 receptors quickly upregulate when antagonized cancelling out any effects of antagonism after the initial memantine adaptation phase.

Wikipedia:

Memantine is an antagonist at alpha-7 nAChR, which may contribute to initial worsening of cognitive function during early Memantine treatment. Alpha-7 nAChR upregulates quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic memantine treatment.[21][24][25]

The mentioned references dont show this in the abstracts as far as i remember, so its probably discussed in the research papers, if this is correct wich i beleive is true as memantine doesnt appear to inhibit nicotine after the adaptation phase, A7 antagonism also inhibits monoamine release by amphetamine, and indeed memantine initially inhibits amphetamine for several people however this quickly goes away after a few days further supporting that after the adaptation memantine doesnt show a negative effect on the A7 receptors.

I'm planning to add in galantamine as it looks very promosing and appears to synergize with memantine, i will keep this thread updated with my experience re memantine and nicotine tolerance.

Also there are several study's showing that nicotine sensitizes the reward pathways, this doesnt mean that nicotine will actually sensitize the reward pathways as this is limited to the D3 receptors wich may or not play a role in reward, D3 receptors have actually been shown to have a opposite effect on CPP (conditioned place preference) compared to D1 and D2 suggesting those receptors could have a opposite effect on reward, altough this can just be limited to spatial learning, CPP is just something associated with reward, this has recently been discussed on mind and muscle.

Edited by medievil, 09 September 2010 - 11:52 PM.

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#35 aLurker

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Posted 10 September 2010 - 12:05 AM


Yeah I've been looking some at memantine but I'd personally prefer to keep the number of drugs down right now, I suppose you've already seen this.
The NMDA angle on nicotine is very interesting. Would this mean that concurrent Piracetam might be a bad idea? :/

Edit: This is why I'd like to keep the number of drugs down... all the damn interactions you have to consider. I don't know what to make of this:

Effects of piracetam and meclofenoxate on the brain NMDA and nicotinic receptors in mice with different exploratory efficacy in the cross maze test

A subchronic administration of the cognition enhancer piracetam (200 mg/kg, once per day for 5 days) increased by 70% the number of binding sites of NMDA receptors in the EL mice. At the same time, this treatment decreased the density of neocortical nACh receptors in both EL and EH mice (by 55% and 40%, respectively).


Edited by aLurker, 10 September 2010 - 12:20 AM.


#36 medievil

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Posted 10 September 2010 - 12:16 AM



Yeah I've been looking some at memantine but I'd personally prefer to keep the number of drugs down right now, I suppose you've already seen this.
The NMDA angle on nicotine is very interesting. Would this mean that concurrent Piracetam might be a bad idea? :/

A few people have confirmed that piracetam and memantine combine very well togheter, piracetam isnt really a NMDA agonist but more of a modulater, i'm guessing it modulates NMDA in brainarea's related to cognition and that it may not intere with the tolerance reducing effect of memantine, but that is just a gues (dont really know exactly how piracetam modulates NMDA), we have no anecdotal reports on this. I'm considering adding piracetam to memantine myself, il have to find out how it will affect its effects on tolerance.

Edited by medievil, 10 September 2010 - 12:17 AM.


#37 dilenja

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Posted 10 September 2010 - 01:38 AM

I guess I'll chime in with my own subjective experience with Galantamine then: I've taken galantamine in dosages as low as 2mg a day and as high as 8mg a day, for a period of about 3 months. I can attest that even at dosages low as 2mg day, a mild discernible nootropic quality was perceivable that felt 'mildly' refreshing and stimulating but unremarkable in and of itself. 4mg doses bi-daily provided me with an even more discernible result of the same nature, and while the effects were certainly pleasing I wouldn't call the results extraordinary by any means. In my experience the benefits were subtle, and felt differently at low dosages than similar experiences I've had using other supplements that increase choline (alpha-gpc, citicoline). I I have unfortunately not tried other acetylcholinesterace inhibitors individually of which to compare to....

In the past I have used nicotine products extensively, and there is no doubt that nicotine was far more activating given the dosing of galantamine I was willing to try. Perceptions with galantamine; 'slightly' improved clarity of thought beginning at 2mg daily, with a window of 4 to 8 hours following dosage. Subjectively felt memory was slightly better with single and bi-daily doses of 4mg than with 2mg. I feel my experience was positive with galantamine in general, and I believe it may have a place in the supplement regimen of those who have already finely tuned their protocols. For me, it didn't have a place in my 'core' regimen because although the effects were pleasant, they did not directly address the fundamental challenges I was seeking to resolve and I felt that continuation would likely distract from objectively evaluating other supplements I intended to try for merit. I didn't perceive any negative effects during my trial and would be open to using this again in my regimen on a trial basis once I am able to further fine-hone the core components.



...


Yes, I spend hours on pubmed and I'm certainly one of those who spend a lot of time obsessing about hypothetical risks. Yet I'm still definitely prepared to take risks, otherwise I wouldn't be here and taking nootropics. All I'm trying to do is find out what risks I'm taking in order to have a clear risk/benefit analysis so I can make a reasonably informed decision, well that and also try to minimize the risks.

An empiric trial wouldn't tell me anything about the long-term risks I might be taking here. In this particular case it might be a good idea though since it is by far the easiest and most reliable way to figure out the benefit part in my risk/benefit analysis and the acute risks seem to be very low. In order to use this long-term however I'd certainly want to research it more thoroughly. I might order some to see if the benefits are noticeable enough to make it worthwhile though so thanks for your input.





#38 aLurker

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Posted 10 September 2010 - 05:59 PM

First time trying nicotine and I love it so far. Ever since this morning when I put on a quarter of a 21 mg patch I've been too busy cleaning my room to post at imminst. That's a good thing (and VERY unusual for me). I ordered a bottle of galantamine a couple of days ago so I might also try that in a week or so.

Well back on topic:
Medievil, I didn't mean memantine and Piracetam, I meant the combination of nicotine and Piracetam and how they might interact. Today I haven't had any supplements besides the 5.25 mg of transdermal nicotine, ALCAR, omega 3 and some pomegranate juice. I might try to combine with Piracetam tomorrow even though I feel quite clueless right now how that combination would work in the long run.

#39 medievil

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Posted 10 September 2010 - 06:08 PM

Yeah i loved it too at first, then the irritability came without any positives, doubling the dose to half a patch was good too, then the same happened, nicotine tolerance is a very real issue, but as ive said so far no problem at all on memantine.

Youll have to see how they would work togheter, i dont see any issues long term with the combination, besides any subjective differences wich you can notice.

#40 Rational Madman

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Posted 11 September 2010 - 05:22 AM

Dosage should be determined by tolerability, and symptoms indicative of reduced nicotinic receptor expression/population. Start at 4mg (TID), and keep titrating until optimal dosage is reached.

Galantamine is a positive allosteric modulator, not an agonist, so it probably doesn't regulate nicotinic receptor expression. Feel free to correct me if this is wrong, but I thought the benefit of PAMs was that they exert their effect outside the homeostatic loop.

You also may have missed our discussion about nAChR modulation occurring at lower dosages, and not at higher ones. Starting at what is probably an effective dosage for this effect and titrating upward based on tolerability is almost certainly counterproductive.

Frankly, I'm not convinced of the perils of acetylcholinesterase inhibition, since there is plenty of evidence supporting the safety of this pharmacological target in healthy subjects.

General tolerability and safety in no way implies that everything is optimal (or even without adverse effect) on a more minute scale. Though it doesn't appear to be as large a concern with the dosages of galantamine we're talking about here, inhibiting the mechanism by which the brain regulates levels of a neutrotransmitter certainly has the potential to throw a wrench into the works. When we're talking about optimizing levels and function of such NTs toward the goal of cognitive enhancement, such concerns would seem to be highly salient.

And as aLurker rightly observes, the approach you advocate really doesn't tell you anything beyond its subjective effects (those that are grossly apparent, anyway).

If you spend hours at PubMed, you'll find contradictory findings on any subject, but I'm convinced that the Imminst population spends an inordinate amount of time obsessing about the contrary findings and hypothetical risks---which as a consequence, perpetuates many neuroses. In sum, take a deep breath, suppress your fears, and conduct a careful empiric trial.

So studies should be used as justification of general safety, but fears should be "suppressed" when research points to potentially adverse effects? That sounds like wishful thinking to me (especially when consideration of research and risk assessment are characterized as neurosis), but in the interest of safety I tend to apply a somewhat lower requirement for evidence to things that can potentially screw me up. Based on most of your previous posts, I'm frankly shocked to hear you saying something like this.

Not to be indelicate, but you seem to have missed the point of this thread. We're discussing the pharmacological research of a very interesting substance, toward the goal of increasing our understanding of its effects. This in no way precludes the "just do it" approach you seem to be advocating here, but rather allows it to be undertaken with better probability of a good, sustainable result. The hypothetical risks here are pretty small, and stated as such.

But really, I think your advice is a little out-of-place in such a theoretical discussion, and I'm pretty sure that no one involved in this conversation really needs to be told any of that. I'm not trying to say that your opinion is invalid, but rather that a stimulating discussion should not be minimized in such a "you guys are thinking about it too much" way. If you have something to contribute toward our understanding of these issues, feel free.


While Galantamine itself does not possess a binding affinity for nicotinic receptors, by mechanistically inhibiting acetylcholinesterase, and thus increasing the availability of acetylcholine---which is an agonist---the administration should upregulate nAChR expression.

Given the title of the thread and it's content, I find it hard to fathom that you thought I missed the gist of the discussion----although time constraints have forced skimming, and eccentricities have compelled the capricious composition of posts in the past. Besides the concern over the ideal dose for maximizing the upregulation of alpha7, thread participants also demonstrated a concern over the safety of acetylcholinesterase inhibition in healthy subjects---which has been a recurring theme whenever this mechanism is discussed. So, I thought it was worth addressing in order temper the enduring concern that hasn't been satisfactorily resolved---although I unfortunately didn't have time to provide any links. Then, I insensitively proceeded to lecture the thread participants on the merits of risk, which was admittedly out of place, but influenced by a growing frustration with an unhealthy fear of risk taking that I've seen displayed repeatedly by members since joining this community, which I feel will pose a significant impediment to our mission of radically improving health outcomes.

As for the just do it approach that you aptly describe, I think my point and motivation was evidently missed due to being less than sufficiently explicit, and mistaken for a careless roulette approach to the concern of alpha7 and general cognitive enhancement through galantamine administration. Although a novel pharmacological target for improving symptoms for a number of disorders, it's not clear that dose dependently maximizing upregulation of alpha7 will yield the best clinical improvement. Furthermore, there isn't a broad consensus on the ideal dosage, and are too many pathological variables that may alter dosage assumptions---such as reduced acetyltransferase activity. So, trying to extrapolate the the ideal dosage from studies may be an inferior method relative to a methodologically sound empiric trial for arriving at the best subjective dose.

Presently, it seems clear that acetylcholinesterase inhibitors can be safely administered to healthy subjects without producing adverse events, but it's effects are are a function of the patient's pathology---and greatly reduced in those unaffected by enzymatic dysfunction. Because of the incidence of minor adverse events, systemic hysteria about unsubstantiated complications, and uncertainty about effective doses, the dosage guideline remains depressingly low---but I believe better results may be achieved at higher doses when combined with other agents. Of course, excess acetylcholine can be neurotoxic, and a complete reduction in acetylcholinesterase could result in asphyxiation and death, but such would require an absurd amount of galantamine, and is more frequently associated with acute exposure to nerve gases or insecticides. There are other potential complications, that I could of course elaborate on, and are undoubtedly occupying many minds, but I would prefer to address them as they're brought up---rather than systematically delving into each one.

Science is replete with contradictory results on human activity, because methodological flaws, author bias, and other independent variables can easily influence the dependent variable. What is disturbing, though, is how we prematurely surrender ourselves to our fears of mortality, and permanently alter our behavior before scientific requirements for proof are satisfied, and without considering strategies to mitigate the danger of an endeavor if there is evidence of it being a worthy one. So, since we're dealing with agents at doses on these forums with weak pharmacological effects and associated with a relatively low and heartening incidence of adverse events, there's no need to hyperventilate every time a confidence dimming study is produced. Since many members on this forum (myself included) have allowed themselves to become disturbed by hypothetical dangers, and have devoted an inordinate amount of energy to maximizing well-being and controlling confounding factors, there is indeed a danger of perpetuating or giving rise to neurosis---which to be clear, I was not meaning to imply that any of the thread participants are neurotic. This preoccupation---as manifested by the thread topic---has the additional danger of furthering social isolation, because many of us become fixated on topics that are alien to the general public. I've encountered this problem repeatedly---for instance, try telling an aesthetically charming and otherwise intelligent girlfriend that you find enchanting that you spent your Saturday researching catechol-O-methyltransferase, which is greatly at odds with your social science background, not imperative to your professional career, and bewildering to the average individual. Luckily, she overlooks my eccentricities, but it can create a gulf, so I have to be careful not to allow desire for life extension to become antagonistic with requisites for happy everyday living. So, there is some wisdom to taking scientifically supported leaps into the dark, because we're not remotely close to arriving at a final understanding of any condition, and because there are opportunity and unintended costs to becoming fixated on these topics---however important we might deem them to be to our welfare.

Edited by Rol82, 11 September 2010 - 07:08 AM.


#41 Rational Madman

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Posted 11 September 2010 - 07:20 AM

First time trying nicotine and I love it so far. Ever since this morning when I put on a quarter of a 21 mg patch I've been too busy cleaning my room to post at imminst. That's a good thing (and VERY unusual for me). I ordered a bottle of galantamine a couple of days ago so I might also try that in a week or so.

Well back on topic:
Medievil, I didn't mean memantine and Piracetam, I meant the combination of nicotine and Piracetam and how they might interact. Today I haven't had any supplements besides the 5.25 mg of transdermal nicotine, ALCAR, omega 3 and some pomegranate juice. I might try to combine with Piracetam tomorrow even though I feel quite clueless right now how that combination would work in the long run.


Indeed, it is a highly motivating substance, but you shouldn't forget about the pleasure of periodic use through other delivery mechanisms. One of my Sunday rituals is to visit one of several park benches with the Sunday editions of the New York Times or Washington Post, and enjoy an Ashton cigarillo or two while eagerly devouring the contents of the papers.

#42 KimberCT

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Posted 11 September 2010 - 11:17 AM

While Galantamine itself does not possess a binding affinity for nicotinic receptors, by mechanistically inhibiting acetylcholinesterase, and thus increasing the availability of acetylcholine---which is an agonist---the administration should upregulate nAChR expression.


I think you're confusing galantamine with the other AChE inhibitors.  Galantamine does bind to nicotinic receptors, although it does so at a different site than acetylcholine and nicotine.

Galantamine Is an Allosterically Potentiating Ligand of Neuronal Nicotinic but Not of Muscarinic Acetylcholine Receptors




#43 medievil

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Posted 11 September 2010 - 04:31 PM

aLurker still want to add i want to warn you about nicotine addiction, chances are you will get completely tolerant with even some negative effects added and without the nicotine you will start to crave it badly, its not a nootropic like all the others, as shown in my study above it causes adaptive changes in the dopamine system simular to addiction to other drugs of abuse.

#44 aLurker

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Posted 11 September 2010 - 05:42 PM

aLurker still want to add i want to warn you about nicotine addiction, chances are you will get completely tolerant with even some negative effects added and without the nicotine you will start to crave it badly, its not a nootropic like all the others, as shown in my study above it causes adaptive changes in the dopamine system simular to addiction to other drugs of abuse.


Yes mommy.

Thanks for your concern but I'm a big boy now (although I'd gladly let you pack my lunch). Perhaps addiction is an issue even without the MAO A inhibition of tobacco or the nicotine spikes from other forms of administration but I'll risk it because it is definitely worth it so far. This is the only thing so far which has actually worked for my motivational issues. I'm actually getting shit done now and it feels awesome.

Tolerance worries me more although I'd be far more worried about tolerance from for instance amphetamine than nicotine as that is far better documented. Do you have any sources for your tolerance claims or are they based solely on your subjective experience (that no doubt is influenced by other substances I'm not taking)? The studies on tolerance I've been looking at looks pretty ok to me, especially compared to other comparable drugs such as amphetamine or methylphenidate. Too bad it's very hard to distinguish as to whether long lasting tolerance to the specific aspect of motivation occurs.

I might consider memantine in the future if I experience any tolerance to the motivational aspects of nicotine, until then I'm more curious as to whether periods without nicotine or combining the nicotine with galantamine would help me avoid tolerance.

#45 medievil

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Posted 11 September 2010 - 06:13 PM

Whaha, big boys get tolerant too :laugh: !

My source is the study i posted on adaptive dopaminergic changes in nicotine addicts, dopamine is yummie, dopamine downregulation is not good!

At that time i was only taking nicotine.

Just go for memantine is what mummy would say!

#46 medievil

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Posted 11 September 2010 - 06:14 PM

Anyway, memantine reversed my nicotine addiction, so its not you would do anything permanent.

#47 aLurker

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Posted 11 September 2010 - 06:28 PM

Ok cool, thanks for sharing. Always nice to know there are options if it stops working.

#48 yowza

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Posted 12 September 2010 - 02:06 AM

Wow. This discussion has gone way too fast for me to keep up with. :)


From the 2nd pg., I'm seeing that there seems to be some ambiguity about Galantamine's positives vs. negatives. I think it's important to try and clear up this ambiguity if anyone's considering centering a nootropics regimen around this.

I typed out a reply earlier this week but wanted to check a few things to see what I could find before pasting it onto this post. Here's what I cound find...



Chrono: I think this is where I got the idea that regulation doesn't occur for nAChR PAMs:
"Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer's disease.
Maelicke A.
Laboratory of Molecular Neurobiology, Johannes Gutenberg University Medical School"

"Allosteric modulation of nAChR is a novel approach, which circumvents the development of tolerance"



What did you think of the Dr. Petrova article?

In one of my previous posts, I organized some of the various quotes of hers interspersed throughout the article into what I interpreted (after reading the full article) as 3 main points explaining that she was trying to get across in terms of categorizing some of the nicotonergic effects acheived from Galantamine (1) nachr upregulation, 2) increased sensitivity/reduced tolerance, 3) neurotransmitter enhancer).
Interesting to see that there are other articles (like the one you referenced in the quote above) supporting one of these points , of increased nicotine receptor sensitivity, that Dr. Petrova seems to be making.

However, in regards to the increased sensitivity/reduced tolerance acheived through alosteric modification of the nicotine receptor, I'd just like to point out that there are different types of alosteric modication of the nachr that can take place.

Galantamine has an effect on a part of the nicotine receptor that's termed a "noncompetitive allosteric activator site" (so galantamine is therefore a "channel activator" or in other words a "positive allosteric modulator"). I tried quoting a part of an excerpt explaining this (also from Dr. Petrova's paper) on my previous post but will now post the entirety just to highlight the different types of allosteric binding sites that seem to exist on the nicotinic receptor.



"Several subtypes of allosteric binding sites exist:
All the types as seen in the Petrova article:

a) Noncompetitive allosteric activator site. Compounds that bind to this site are termed channel activators, as they enhance channel opening and ion conductance. They include cholinesterase inhibitors such as physostigmine, galantamine, etc. It is suggested that this class of receptor primarily functions to enhance nAChR activity induced by the binding of ACh at the classical site.

b) Noncompetitive allosteric inhibitor site. Ligands binding here inhibit ion channel function and include chlorpromazine, ethanol, local anesthetics, barbiturates etc. Ethanol produces a dose-related decrease in nAChR number, and chronic ethanol treatment also partly attenuated nAChR upregulation produced by nicotine treatment of the cells.

c) Steroid-binding sites. Steroids desensitize nAChRs and produce tolerance to nicotine

d) Dihydropyridine site.

e) Additional allosteric modulation of nicotinic receptors. Desensitization of the nAChR ion channel via phosphorylation by protein kinase A, protein kinase C, or tyrosine kinase."



From my interpretation, the only kind of allosteric modification that seems to sensitize/avoid tolerance is the "noncompetitive allosteric activator site"; this is where Galantamine falls in. It's interesting to see that every other allosteric binding site seems to desensitize the nicotine receptor (although I'm not sure what effect the Dihydropyridine site has). Therefore, it's not just any kind of allosteric modification that can cause sensitization...



Chrono: Galantamine is a positive allosteric modulator, not an agonist, so it probably doesn't regulate nicotinic receptor expression. Feel free to correct me if this is wrong, but I thought the benefit of PAMs was that they exert their effect outside the homeostatic loop.


Going over the 3 main points (mentioned above) that I gleaned from the Petrova artice, I'd have to agree with Chrono as everything seems to support his conclusion that Galantamine's Positive Allosteric Modulation of nicotine receptors falls outside the homeostatic loop. However, recall that this mechanism serves to also act as a "neurotransmitter enhancer" (as mentioned in my previous post in which I've quoted what I could find on this so far...). There could always be some downstream effect that could feedback to desensitizing an nachr receptor in a roundabout way... However, I believe Chrono's right in at least the direct sense.


KimberCT: My understanding is that, PAMs increase the effect when a separate agonist binds to the receptor. For example, benzodiazepines are GABA-A PAMs. They cause the ion channel to open wider and/or for a longer period of time only when GABA or another agonist binds to the receptor. In the case of benzos, this potentiation of GABA causes rapid downregulation of the receptor.


edit: The above is just an example of one group of PAMs. This doesn't necessarily mean that galantamine will cause downregulation of nicotinic receptors.


Thanks Kimber CT, this post really got me thinking...

While the "positive allosteric modulation" of nicotine receptors does seem to fall outside of the homeostatic loop (as chrono suggests; at least for the most part), it has to be remembered that besides working as a "PAM" on nicotine receptors, Galantamine also functions as an acetylcholinesterase inhibitor.

Let me explain... As we know, the neurotransmitter Acetylcholine is non-selective and hits all Acetylcholine receptors in the brain (both nicotonergic as well as muscarinic). Inhibiting the enzyme ACHe (through Galantamine's dual mode of action when not taken at smaller dosages) causes more acetylcholine to build up in the brain, hence more acetylcholine receptors (both muscarinic and nicotonergic) being activated. Therefore, without the enzyme acetylcholinesterase to keep acetylcholine levels in check, acetylcholine is now acting as a sort of cholinergic agonist. Factoring in Galantamines "positive allosteric modulation", this would potentiate the acetylcholine to act as even more of an agonist on these nicotonergic receptors.

Therefore, while the Acetylcholine would be functioning as an agonist already (due to the enzyme inhibiting aspect of Galantamine) the Positive Allosteric Modulation (via a similar mechanism to what Kimber CT described) on nicotine receptors would make Acetylcholine an even more potent agonist at nicotonergic sites.


With this information in mind, this raises the question, could Galantamine downregulate nicotonergic receptors not due to it's "positive allosteric modification" mechanism but instead due to the ACHe enzyme inhibition? Also, could this desensitize the nicotine receptor?

To answer the 1st question, ff this were any other receptor (such as the GABA example KimberCT gave above) then the answer would be yes. However, as outlined in Dr. Petrova's paper (I listed this under "point number 1" I saw in her article about nicotonergic upregulation), the answer is actually no because as quoted ""Nicotinic receptors go against the generally accepted paradigm in that overexposure to agonists produces receptor downregulation, and overexposure to antagonist produces receptor upregulation. In particular, long-term exposure to nicotine results in an increased number of nAChRs in the brains of humans."

However, to answer the 2nd question, I've read through various sources that while nicotine (a nicotonergic agonist; as explained above in this post, Galantamine also acts as a nicotonergic agonist when it's dual mode of action is in full effect) upregulates nicotonergic receptors, it can also desensitize them (the upregulation may be a compensatory mechanism in response to the desensitization maybe?).

With this in mind, Galantamine at a lower dosage (with just the PAM effect) would seem to sensitize nicotine receptors but this is only cause there's limited agonist action (due to limited acetylcholinesterase inhibition) it seems.

Edited by yowza, 12 September 2010 - 02:52 AM.


#49 yowza

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Posted 12 September 2010 - 04:02 AM

I organized some of the various quotes of Dr. Petrova's interspersed throughout the article into what I interpreted (after reading the full article) as 3 main points explaining that she was trying to get across in terms of categorizing some of the nicotonergic effects acheived from Galantamine (1) nachr upregulation, 2) increased sensitivity/reduced tolerance, 3) neurotransmitter enhancer).

Based upon what I just ended my previous post on (nicotonergic agonism vs. nicotonergic PAM effects), I'd like to make some modifications to 2 of these 3 points (The third major benefit; neurotransmitter enhancment aspect of Galantamine and nicotonergic receptors in general I'll save for looking into later).


1) Allosteric Modulation component (of Galantamine) is what Increases Nicotine Receptors:

Dr. Petrova: "Scientific studies find that nicotine induces an upregulation of nAChR sites in human brains, including brains of AD patients."

"Nicotinic receptors go against the generally accepted paradigm in that overexposure to agonists produces receptor downregulation, and overexposure to antagonist produces receptor upregulation. In particular, long-term exposure to nicotine results in an increased number of nAChRs in the brains of humans."


Dr. Petrova Nicotine has a neuroprotective effect against Ab deposition and increases the expression of high-affinity nerve growth factor (NGF)."


The heading I tried to group these quotes under should have read Allosteric Modulation component of Galantamine helps facillitate an Increase in Nicotine Receptors since PAM doesn't seem to cause the increase but simply facillitate it (nicotinic receptor agonists like nicotine or acetylcholine are the main cause behind the receptor increase it seems).

Before (When I initially read the article), I got confused because, at times, Dr. Petrova seemed to be using nicotine and Galantamine interchangeably (since both have effects on nicotonergic receptors). She's doing this since she's referring to alzheimers patients who take higher dosages and therefore get galantamine's dual effect (the pam mechanism interacting with the ache mechanism). However, the PAM mechanism by itself (when Galantamine is taken at lower dosages) doesn't seem to significantly increase nicotine receptors.


It should also be noted that the rabbit study (posted by aLurker on the 1st pg. of this thread) probably saw increased nicotine receptors in the rabbits due to the dosage being given at a level where Galantamine could have it's dual mode of action. This makes me think that the only way receptors would probably significantly increase from Galantamine (if taken at a lower dosage to avoid the ACHe inhibiting effect) would maybe be if Galantamine was taken with nicotine or some other substance that would potentiate agonist action.









2) Allosteric Modulation of nACHR (nicotine receptor) is what sensitizes them:

Dr. Petrova: "What does galantamine do to improve the symptoms of AD patients? Gordon Wilcock has said that "to halt the disease, you have to stop the brain cells from being killed." Galantamine rescues brain cells from death. It was found that a few cholinesterase inhibitors, including galantamine, produce beneficial effects even after drug treatment has been terminated.29 These effects assume modes of action other than mere esterase inhibition and are capable of inducing systemic changes. Allosterically potentiating ligands sensitize nicotinic receptors by increasing the probability of channel opening induced by acetylcholine and nicotinic agonists and by slowing down receptor desensitization.30 Allosteric modulation of nAChR is a novel approach which circumvents the development of tolerance.


While Allosteric Modulation of nicotine receptors helps sensitize them. I now think this effect obtained from Galantamine may be slightly more complicated... If taken at a dosage level where there's lots of ACHe inhibition, the PAM mechanism would act as a primer encouraging further agonist action (similar to the PAM mechanism that kimber CT describes above). I'm guessing that sensitizing in this regard (as a primer to engourage further agonist action) would cause the opposite to happen (desensitization of the nicotine receptor).

Smokers have an upregulation in nicotine receptors but also may have their nicotine receptors desensitized.
http://www.ionchanne...act/pm/15914250. There's no reason to think it would be different with a pharmaceutical form of Galantamine taking into account it's dual effect that occurs at regular dosage levels (although not at very low dosage levels).



In summary, this is what I can make out about the "PAM"mechanism:
a) When PAM working alone, nicotine sensization could occur (doesn't seem to cause upregulation by itself though I'm guessing?)

b) An agonist at nicotonergic sites (generally speaking) seems to cause desensization, which may encourage the whole increase in nicotine receptors, as discussed above, to compensate for this


C) If PAM is present in combination with an agonist, it seems like the PAM would act as a primer (possibly exacerbating or keeping the receptors sensitized depending on the amount of agonist action present?).

For someone with alzheimers the nicotine/galantamine combo may be a good idea but I'm guessing that, for a healthy person, it could potentially cause a chaotic effect unless carefully controlled. The best way to get around these issues seems to be to play with the PAM:agonist ratio (both should be low; but PAM should be higher).

Edited by yowza, 12 September 2010 - 04:38 AM.


#50 Rational Madman

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Posted 18 September 2010 - 01:18 AM

It should have been readily apparent, but I think varenicline might be the most effective agent for achieving the end goal of this thread. Either that, or Bupropion, which should result in receptor upregulation in a manner similar to Memantine administration. How one attains either is another question, and probably should be explored through private communication.

Edited by Rol82, 18 September 2010 - 01:20 AM.


#51 yowza

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Posted 18 September 2010 - 04:53 AM

It should have been readily apparent, but I think varenicline might be the most effective agent for achieving the end goal of this thread. Either that, or Bupropion, which should result in receptor upregulation in a manner similar to Memantine administration.


You bring up some very interesting points although I wish you'd expand on them a little... Could you elaborate more behind what you see in Chantix (veronicline)? I think I might know where this is coming from but would like to hear your thoughts surrounding this...?

Seeing as how nicotonergic agonists cause upregulation as opposed to downregulation, how would having an antagonistic effect on nicotine receptors still cause upregulation? Did you mean Buproprion caused sensitization instead?

Edited by yowza, 18 September 2010 - 05:19 AM.


#52 medievil

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Posted 18 September 2010 - 01:55 PM

Varenicline is a partial agonist of the α4β2 subtype of the nicotinic acetylcholine receptor. In addition it acts on α3β4 and weakly on α3β2 and α6-containing receptors. A full agonism was displayed on α7-receptors.[4]
Acting as an agonist varenicline binds to, and partially stimulates, the receptor without creating a full nicotine effect on the release of dopamine. Varenicline also competitively binds to α4β2 receptors blocking the ability of nicotine to stimulate the central nervous mesolimbic dopamine system.

Nicotine wins for those looking for a dopamine boost.

#53 yowza

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Posted 18 September 2010 - 09:10 PM

Varenicline is a partial agonist of the α4β2 subtype of the nicotinic acetylcholine receptor. In addition it acts on α3β4 and weakly on α3β2 and α6-containing receptors. A full agonism was displayed on α7-receptors.[4]
Acting as an agonist varenicline binds to, and partially stimulates, the receptor without creating a full nicotine effect on the release of dopamine. Varenicline also competitively binds to α4β2 receptors blocking the ability of nicotine to stimulate the central nervous mesolimbic dopamine system.

Nicotine wins for those looking for a dopamine boost.


I don't think dopaminergic enhancement was the "end goal" that Rol82 was referring to (although this is certainly a downstream effect of nicotonergic enhancement). I saw that same quote over on wikipedia too (http://en.wikipedia....iki/Varenicline). I'm glad you mention it though.

---------------------------------------------------------------------------------------------------------------------------------------------------


On paper, chantix certainly seems like it would have cognition enhancing properties similar to some of the other nicotonergic partial agonist drugs in development that usually seem target either the a4b2 or the a7 type nicotonergic receptors.

Rol82, do you have any more you've found besides the basic mechanism mechanism behind chantix that either:
a) Shows it as having a significant cognition enhancement value for non-smokers? or
b) Showing in what way it effects sensitivity and/or amounts of certain nicotonergic receptors?


---------------------------------------------------------------------------------------------------------------------------------------------------
I found some more info. connecting to Chantix's mechanism of action:
I used to think "partial agonist" only meant any chemical that selectively aimed it's agonist action towards a certain subtype of nicotonergic receptor as opposed to every kind of nicotonergic receptor (as nicotine does). However, here's more to it than that. Here's a more accurate definition of what the term "partial agonist" truly means:

http://en.wikipedia....Partial_agonist
Posted Image

Partial agonists (such as buspirone, aripiprazole, buprenorphine, or norclozapine) bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonistic effects - when both a full agonist and partial agonist are present, the partial agonist actually acts as a competitive antagonist, competing with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone.[1] Clinically partial agonists can activate receptors to give a desired submaximal response when inadequate amounts of the endogenous ligand are present, or they can reduce the overstimulation of receptors when excess amounts of the endogenous ligand are present


Consider the "mechanism of action" behind Chantix (described in the quote posted by medieval; about full agonism at a7 receptors vs. partial agonist at other nicotonergic receptors). Now, link this to the underlined part of the above quote. Maybe this is why chantix doesn't seem to be used to provide cognition enhancement?

Edited by yowza, 18 September 2010 - 09:26 PM.

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#54 medievil

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Posted 18 September 2010 - 09:53 PM

when both a full agonist and partial agonist are present, the partial agonist actually acts as a competitive antagonist, competing with the full agonist for receptor occupancy and producing a net decrease in the receptor activation observed with the full agonist alone.

Yeah, when your taking the stuff with something that increases acetylcholine you can cause a antagonistic effect, but that also depends on the intrinsic activity of this stuff, and how many receptors are being activated by the extra acetylcholine.

#55 Rational Madman

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Posted 20 September 2010 - 12:57 AM

Some good points have been made, and before I address the questions about varenicline, I'll have to delve a bit further. There is some evidence, however, that the monotherapeutic use of varenicline has cognition enhancing properties, and because of its affinities for nicotinic receptors, it is being investigated for use in patients suffering from schizophrenia, Alzheimer's, and other conditions characterized by mild cognitive impairment, but the outcomes are mixed. Interestingly, when combined with bupropion, in concert, both deliver better outcomes than monotherapy, but without the full texts, I'm unable to determine the cognitive effects of this combination. But, I'm very curious, and may experiment should I encounter confidence brightening findings about this combination. Varenicline also carries the risk of promoting behavioral disturbances and suicidal idealation, which has dampened my enthusiasm somewhat, but adjunctive 5ht2a/c antagonism should resolve that problem. For now, though, I'm on the Rasagiline train, since I've concluded that it's safer than many feared, and have been heartened by a friend's experimentation with the substance. For cognitive enhancement, alpha 7 upregulation is certainly important, but there are other pharmacological targets that need to be considered, and I intend to personally investigate over the course of several months.


[moved general discussion of neuropsychopharmacological targets to rol82's regimen thread]

Edited by chrono, 21 September 2010 - 08:28 AM.


#56 medievil

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Posted 20 September 2010 - 06:59 PM

I doubled my nicotine dose, from half a patch to a full one today, lets see how it goes.

Soon will be adding galantamine.

#57 chrono

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Posted 21 September 2010 - 08:32 AM

Since a conversation about essentially every possible target for neurochemical enhancement seems likely to hinder discussion of the topic at hand, I moved the last 12 posts to rol82's regimen thread.

I've done a bad job keeping up with discussions this week, but I hope I can add a few points soon when I'm not quite so tired. :-D

Edited by chrono, 21 September 2010 - 09:09 AM.


#58 medievil

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Posted 21 September 2010 - 01:43 PM

Nicotine seems to be definatly calming, thats what i like the most about it (and came apperant when i moved to a full patch).

#59 KimberCT

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Posted 21 September 2010 - 02:07 PM

Nicotine seems to be definatly calming, thats what i like the most about it (and came apperant when i moved to a full patch).


It's very very interesting that's for sure.  The last couple nights I've had a bit of snus after dinner.  One portion results in a nice, relaxed yet stimulated feeling.  Two portions is a bit too stimulating, making me jittery and exacerbating my tremor.  In either case, however, my anxiety is completely gone.  I've never been "jittery" without high anxiety before.


Note that I'm also taking 4mg galantamine twice daily and 10mg memantine twice daily.  The galantamine is a new addition.  I don't really notice much of anything from it alone.

After using snus Friday night, Sunday night, Monday night, there is a definite craving for it during the day today.



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#60 medievil

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Posted 21 September 2010 - 02:09 PM

Yeah,

I'm adding in galantamine in the near future, guessing it will be an interesting combo.




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