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Acetylcholine Has Negative Effects On Gonadal Steroidogenesis

  1. Choline and acetylcholine are another topic that often pops up online. Cholinergic drugs are still the main "treatment" for Alzheimer, even though all of them are abject failure clinically. Ray has written about the excititoxic properties of acetylcholine, and how estrogen manifests its effects through the cholinergic system. Finally, his latest articles on his website is about the role of the cholinergic system in the establishment of learned helplessness.
    As you can see from the study below, activation of cholinergic "receptors" by nicotine or endogenous acetylcholine inhibited testicular synthesis of androgens.

    Nicotinic cholinergic agonists inhibit androgen biosynthesis by cultured rat testicular cells. - PubMed - NCBI
    "...Concomitant treatment of testicular cells with nicotinic cholinergic agonists (lobeline, nicotine, and dimethylphenylpiperazinium iodide) inhibited hCG-stimulated androgen biosynthesis in a dose-dependent fashion, with IC50 values of 3 X 10(-5), 1.7 X 10(-4), and greater than 10(-3) M, respectively. In contrast, two muscarinic cholinergic agonists, muscarine and bethanechol, failed to inhibit androgen production at concentrations up to 10(-3) M. A ganglionic nicotinic antagonist (hexamethonium), but not a skeletal muscle nicotinic antagonist (decamethonium), partially blocked the actions of lobeline. Lobeline (10-4) M) decreased hCG-stimulated testosterone production (50-75%) throughout the 2-day culture period; however, this inhibition was reversible upon removal of the drug. Lobeline also inhibited hCG-stimulated cAMP accumulation as well as testosterone production induced by cholera toxin (65% inhibition), forskolin (50% inhibition), or (Bu)2cAMP (70% inhibition). Lobeline inhibition of hCG-stimulated testosterone production was accompanied by decreases in medium accumulation of 17 alpha-hydroxypregnenolone (75%), 17 alpha-hydroxyprogesterone (85%), dehydroepiandrosterone (50%), and androstenedione (61%); however, the medium content of pregnenolone and progesterone were unchanged. Additional experiments demonstrated that lobeline suppressed the conversion of exogenous progesterone to testosterone, but did not affect the conversion of exogenous 17 alpha-hydroxyprogesterone to testosterone. These results indicate that nicotinic, but not muscarinic, cholinergic agonists inhibit androgen biosynthesis through selective inhibition of 17 alpha-hydroxylase activity. Thus, endogenous acetylcholine may be involved in the negative regulation of testicular steroidogenesis."
     
  2. I thought nicotine increased 5-alpha reductase production? Hasn't it been well documented?
     
  3. Do you have some studies? If these agonist inhibit androgen synthesis by blocking the first step downstream from pregnenolone (as the study days) than even if nicotine upregulates 5-AR it won't be much good.
     
  4. What are some of the better anti-cholinergics one can take? I've been dealing with blurry vision <more than usual> for awhile now, and someone told me that too much acetylcholine can be a possible cause of this. I'm a smoker too, which only compounds matters.
     
  5. Benadryl is a great one and it is OTC. Cypro is also anticholinergic. Caffeine is another one.
     
  6. Does l theanine have any use in blocking acetylcholine as i seems i to do very well with both l theanine and cypro? I take them in the evening and it seems to be the next day I feel very clear headed and energetic!

    Regards
     
  7. So... Don't rub nicotine on your balls.

    Isn't up regulation of receptors a good thing? I know you have another post where caffeine up-regulates nicotinic receptors. Do you think that if receptors are made more sensitive, that nicotinic receptor agonists therefore do more harm in steroidogenesis? Perhaps pairing smoking with coffee isn't for the best if so.


    So far I've been under the impression that tobacco is useful in small amounts, but if this is really the fact, then a lot of the other information kind of falls off the table.

    Maybe @Dopamine or @pboy have some points in opposition regarding this controversial topic.
     
  8. Whoa there, no need to jump to conclusions! Always keep the ball rolling, so to speak.
     
  9. @haidut what are your thoughts on Scopolamine? There were some studies showing rapid anti depressant action on par with Ketamine. I tried the patch and only got the classic anti cholinergic side effects.

    Phosophilipid and citi choline supplements have, in the past (pre peat) made me seriously depressed, sheer agony almost to the point of hallucination. The occsional organic cigarette will make me anxious and melancholy (mixed state)

    I'm bipolar 2 and I continue to wonder about the anti cholinergic approach. History of learned helplessness > paxil > hyperprolactinemia > bipolar disorder via kindling effect? > reliance on adderall/klonopin to stay reasonably functional. Possible benefits with 5adhp will update soon
     
  10. @haidut

    does this mean that Gonadin could have possible anti cholinergic effect?
     
  11. I think I remember reading that caffeine and theacrine increase acetylcholine?

    For example Caffeine enhances acetylcholine release in the hippocampus in vivo by a selective interaction with adenosine A1 receptors. - PubMed - NCBI

    Also Prenatal caffeine ingestion induces aberrant DNA methylation and histone acetylation of steroidogenic factor 1 and inhibits fetal adrenal steroidog... - PubMed - NCBI
     
  12. The methylxanthines are usually antagonists at the nicotinic (cholinergic) receptors. I posted a study on caffeine's antagonist on serotonin and some other receptors. See below.
    Caffeine Is A Serotonin Receptor Antagonist
     
  13. Don't see the connection. Why would it have anticholinergic effects?
     
  14. i get the idea its an issue of if the nerves will be overstimulated or not, which would depend on the persons innate capacity to handle that, their current situation, and maybe current nutritional status...theres no doubt nicotine can 'frustrate' or one might think its doing that, probably a cholinergic thing, and that theanine can temper this which indicates a glutamic or acetylcholine connection. I think that system has to do with clearing obstacles in life and moving forward, and it will try to rev up the capacity to do that, but what if the person is in a really tight or 'overwhelmed' situation, then ramping that up wouldn't necessarily help at a certain point and would 'frustrate' the nerves which might send stress signals and the signal that 'I cant do what I need to do' or something like that but really its just are you progressing its sort of metaphoric for life, you cant necessarily do everything at once but just seeing and making progress is really what matters as that is the only way to lead to solutions. Over the years tobacco use has, its why it spiritual also, you kind of learn to just progress no matter what instead of letting the enormity of any situation be overwhelming...I can see the propensity of too much acetyl to 'frustrate' and maybe retrograde fire due to the reasons mentioned above...trying to force something faster than can tangibly be done, or resolve something nervously in the same way, but the person can become aware and train so to speak to progress in flow...id never purposefully want to inhibit that its like certain constipation in life if you do so to speak...better to try to find the most efficient spot and have good mental control and outlook to progress through anything no matter what reason or the environment might say is the case...its like if something is going to take a herculean effort that might span some time, most would think or say or cast doubt or say its not possible or not worth it, but I think that somehow leads to a bti of learned helpless or lower thyroid or worse off serotonin, or you can seem foolish and go through with it anyways, ultimately leading to the progress, by just doing things as efficiently and the most you can in time and see things part along the way. So I think its a bit reductionist but get the point its making...I see this playing out in life a lot. Its basically do you progress no matter what without blowing out or latch onto all the reasons that wouldn't be possible and therefore alter course or cast doubt for the sake of it being easier nervously
     
  15. I am wondering about the concentration of nicotine applied. Both caffeine and nicotine are toxic in high concentrations. These chemicals are both produced in plants for similar reasons- to kill or paralyze predatory insects and inhibit growth of competitive neighbouring seedlings. They are likely pesticides by nature. Their pro metabolic effects probaly derive from being a mild stressor in low doses (like exercise) some stress is needed for growth, development, mental sharpness/fortitude etc... probaly any toxic chemical will inhibit androgen synthesis. "Toxic" being a vague word for overly stressful.

    My understanding is that this test was performed on cells in a petri-dish so it may not reflect accurately how nicotine effects the body "in vivo". Especially considering how nicotine is processed by enzymes in the liver rather quickly and would never be found in the blood (or testicles) in extremely high concentrations except upon overdose which is not the point. Again I don't know what the concentration in this study amounts too nor would it matter really because it is not a natural setting for exposure.

    Nicotine desensitizes acetylcholine receptors and subsequently causes upregulation of receptor density [1] This is well known. You have posted studies that show caffeine does the same thing and said this:
    Caffeine Is A Serotonin Receptor Antagonist
    The densities of cortical β1 and cerebellar β2 adrenergic receptors are reduced by ca. 25%, while the densities of cortical α1 and α2 adrenergic receptors are not significantly altered. Densities of striatal D1 and D2 dopaminergic receptors are unaltered. The densities of cortical 5 HT1 and 5 HT2 serotonergic receptors are increased by 26–30%. Densities of cortical muscarinic and nicotinic receptors are increased by 40–50%. The density of cortical benzodiazepine-binding sites associated with GABAA receptors is increased by 65%, and the affinity appears slightly decreased. The density of cortical MK-801 sites associated with NMDA-glutaminergic receptors appear unaltered.

    If both caffeine and nicotine increase nicotinic acetylcholine receptor density then my understanding is that chronic low dose exposure to both should be lowering acetylcholine... I think that to say nicotine increases acetylcholine may not necessarily be true just because it is an agonist of nicotinic acetylcholine receptors.

    Now I may be completely off on this but this is just my limited analysis and understanding of an obviously complex topic. For the record I haven't been using caffeine or nicotine because i'm unsure about both of them.
     
  16. gonna make what I wrote simpler...I think it does matter, theres a gap in what indivuduals can handle based on mental constitution, will, nutritional status current and life situation, and it basically pushes or tries to move things waste out and energy outward and active, and depending on the situation can the person handle that or not? the amount of tobacco in cigarettes and cigars is probably excessive its why people just 'puff' it, sort of a waste to me, but its really a matter of if pressure is put due to the function being impeded or not perfect cause of various factors, does the person 'give up' or not even totally give up just lower their drive, or do they stay focused and try to do something about it actively physically mentally or otherwise...not everything is so simple as 'good or bad' though you could say its always ultimately good but peoples perspectives at the time might not agree, and of course...well things a lot of times have to have a time/experience factor in there so if you put a huge amount of push prematurely to its ability to be digested so to speak it might manifest as excessive nerve pressure, but also can be a powerful exposer of what needs to be resolved
     
  17. I did not say that nicotine increases acetylcholine. Where did you see me saying that? Since it is an agonist of the AChE receptors it is expected to trigger a feedback mechanism and it seems that it does that - i.e. increases levels of acetylcholilnesterase, which breaks down acetylcholine.
    http://www.jneurosci.org/content/jneuro/3/4/871.full.pdf

    So, yes, nicotine exposure should lower acetylcholine levels but nicotine itself is a powerful agonist of those same receptors and the net effect is probably still heavily cholinergic. This is probably one of the reasons Big Pharma had (misplaced) high hopes for nicotine as treatment for Alzheimer and it badly failed in pre-clinical trials.
     
  18. I agree, and have been thinking of creating a post in regards to this.

    Coffee, Marijuana, and Tobacco all are stressors of some sort on the body, and if inadequately supported nutritionally or calorically, it usually ends up putting the person in a worse state.

    This is also seems to mirror as to how low doses of each are stimulating, whereas high doses are sedating.

    Is perhaps the boost in pregnenolone and progesterone not benefitting the body and instead just a response to stress being caused upon the body?

    I understand there are studies showing tobacco for example raising glutathione 2x or so the normal amount as well as an example.




    Id imagine that people in an ideal state would have more pregnenolone sulfate, and overall stored forms of these beneficial higher functioning hormones rather than being active in the body and being released all the time.


    Even if we acclimate to these stressors, will it continue to be more and more beneficial to keep adding on? At what point do we decide that the overflow of all these drugs into our systems are good enough?

    Do we just maintain our use of these substances or go clean?

    just some general questions to anyone willing to awnser; not just to @Dopamine.
     
  19. L-tyrosine Administration Increases Acetylcholinesterase Activity In Rats
    Could it then help with learned helplessness?
     
  20. There are many things that have this effect. I don't know if tyrosine alone would be sufficient but combined with BCAA may have some mood boosting effects by lowering serotonin.
     
  21. I wasn't directing it at you when I said:
    I think that most people in general have the idea that ACh increases cognition and nicotines pro cognitive effects must stem from increasing ACh. I've seen that claim many times on reddit etc...
     
  22. I have been experimenting with ashwaganda and it has properties that inhibits acetylcholinesterase while also elevates serum testosterone and semen production, so like a lot of things in the peat community this also seems very contradictory. @haidut do you recommend taking ashwaganda for the testosterone stimulating effects or should it be avoided for the reasons you were mentioning?

    Withanolides, a new class of natural cholinesterase inhibitors with calcium antagonistic properties. - PubMed - NCBI
    "the withanolides 1-3 and 4-5 isolated from Ajuga bracteosa and Withania somnifera, respectively, inhibited acetylcholinesterase "
    Clinical Evaluation of the Spermatogenic Activity of the Root Extract of Ashwagandha (Withania somnifera) in Oligospermic Males: A Pilot Study. - PubMed - NCBI

    "Improvement in these parameters was minimal in the placebo-treated group. Furthermore, a significantly greater improvement and regulation were observed in serum hormone levels with the Ashwagandha treatment as compared to the placebo"
     
  23. I am a pfs sufferer and I have gotten increased libido from smoking tobacco or chewing nicotine. However it also made me very tires. So that might play into increased 5ar emzyme but lower total test levels.
     
  24. @dilantinoid Updates? What have you discovered about Scopolamine?
     
  25. Nothing positive, lost interest. Was tried under the supervision of a Mt. Sinai pyschiatrist.
     
  26. What about thiamine? I read that it increases acetylcholine too.
     
  27. Bump that question.

    I quite nicotine couple days ago, now about to shake caffeeine as well.

    Defiently want to quit small thaimine doses aswell if that is the case.
     
  28. Old thread, but I just came across and I have an answer.

    Thiamine does seem to be involved in acetylcholine release.
    Possible involvement of thiamine in acetylcholine release

    And thiamine deficiency leads to acetylcholine production impairment.
    Possible involvement of thiamine in acetylcholine release
     
  29. What’s your latest thinking on this ? To me, it does seem like nicotine inhibits androgen synthesis from how I feel but I also read this from you recently.

    “Nicotine also inhibits the enzyme 3a-HSD, which degrades DHT into the less potent androstanediol. So, if it does increase 5-AR , the combination of the two would make it quite pro-androgen. The study below shows this effects is from physiological doses achievable by a smoker or a person using nicotine gums/patches.
    Nicotine and cotinine effects on 3 alpha hydroxysteroid dehydrogenase in canine prostate. - PubMed - NCBI

    And nicotine is also an aromatase inhibitor.
    Nicotine blocks brain estrogen synthase (aromatase): in vivo positron emission tomography studies in female baboons. - PubMed - NCBI
    Nicotine alters the expression of molecular markers of endocrine disruption in zebrafish. - PubMed - NCBI
    Potential contribution of aromatase inhibition to the effects of nicotine and related compounds on the brain. - PubMed - NCBI

    Peat said in a recent email exchange that nicotine's biggest benefit is probably on digestion, but I think those steroidal anti-estrogenic and proandrogenic effects are also something to keep in mind. Btw, even a single dose of 4mg nicotine daily was enough to see GI benefits and in fact a medical student famously took up smoking to cure his Crohn's disease.
    'Doctors don't always know best:' Student claims he cured debilitating bowel disease by taking up smoking | Daily Mail Online“
     
  30. He should've just looked into megadose vitamin D3.
     
  31. is nicotine in small amounts worth taking for the digestive, anti estrogen pro 5ar benefits then? what would be the safest way to ingest nicotine and what would be the best safe dosage daily or every other day? im new to nicotine, from my understanding you shouldnt be smoking it and should be looking for other ways to ingest it?
     
  32. I wouldn't know. Those that take it tend to use a patch.