I must say your understanding of everything you have commented on in this forum is textbook perfect.
My interest in PNS actions derived partly from the study of mild cognitive impairment and alzheimers in which the primary neurotransmitter, acetylcholine, is lower than in the population. The first line of treatment is usually an acetylcholinesterase inhibitor. It is not uncommon for hypersexuality to develop when using these drugs. I have avoided experimentiing on myself because Ach`s action on the bronchii is constrictory and I have a sig degree of COPD, PHT and asthma. My libido and penile sensation has been somewhat less than par lately. So nonetheless, I took ~4mg donepezil last night and awoke to some nice wood for a change with no change in breathing. As far as I know no one has explored the benefits of the acetylcholinesterase inhibitors in terms of libido and sexual performance. I would expect an increased liklihood oh PE to occur which may negate the gains or could perhaps be offset by other druge. My usual treatment for PE is tramadol which binds not only to several of the opiate receptors but exerts a stimulatory effect on serotonin as well- very effective.
Looking forward to your thoughts.
I know for a fact that Nicotine withdrawal can cause ED and decreases penile sensitivity which would support the role of AcetylCholine in erectile function. However, stimulus is still needed in order for the body to send the AcetylCholine signal to genitals and associated organs/smooth muscle. The body generally produces a large amount of AcetylCholine, however it can be low in certain areas and high in others. Amphetamines for example increase the concentration of Acetylcholine in the striatum but lower it in other areas.
AC (acetylcholine) plays a large role in erectile function, however I find it would be unlikely that it is the sole reason for ED as other symptoms would develop indicative of low acetylcholine along with it as it controls all or almost all muscular contractions in the body as well as plays a large role in memory. I wouldn't suggest the long term use of a cholinasterase inhibitor due to potential overdose and other problems, especially an interaction with pre-existing COPD. This is why I instead recommended Piracetam or Pramiracetam. It has been show to be neuroprotective, improve cognition, Alzheimer's symptoms, wellbeing and libido all while having zero toxicity or withdrawal effects. It however, will have more subtle effects than a cholinasterase inhibitor.
To test whether you have low AC or that AC may be playing a role in ED one could perform a simple test of chewing a moderate to large dose of Nicotine gum before/during sex as Nicotine is a very powerful cholinergic agonist.
Mirapex (pramipexole hcl) frequently has the side effect of increased libido and sexual function along with not uncommon cases of hypersexuality. Mirapex will increase dopamine action (as it is a powerful multi-receptor dopamine agonist), lower prolactin and also
lower acetlycholine. Giving more support to the theory that stimulation is needed in order for acetylcholine to perform it's action in erectile function and that the body is capable of producing enough acetylcholine
for that specific purpose upon
stimulation. The cholinasterase inhibitor likely had an effect similar to a PED-5 inhibitor which was to essentially make the body more sensitive to sexual stimulation, but not provide actual sexual drive directly so to speak. In males sexual stimulation is different from females in that, because a man is "turned on" he will get an erection, but also, because he has an erection, he will become "turned on". This is the case in females in that sexual stimulation will cause lubrication etc, but random vaginal relaxation and lubrication secretion will not cause them to be "turned on".
Thus, in theory, acetylcholine, like PDE-5 inhibitors improve male libido through an indirect pathway and compensate for lack of sexual stimulation on the part of the CNS. It is also interesting to note that a PDE-5 inhibitor and a substance that increases Acetylcholine would work synergistically. Acetylcholine stimulates the release of Nitric Oxide, and a PDE-5 inhibitor prevents it from degrading. I actually wonder now if prolactin has an antagonistic or otherwise deleterious effect on the acetylcholine receptors in the genitals, as people with high prolactin still seem to maintain at least some libido (the low libido likely being due to the low dopamine caused by the high serotonin not the prolactin itself) but often lose the ability to have an erection, and have lessened penile sensitivity which makes it difficult to achieve orgasm for some (especially women). It is less likely that it has any direct effects on PDE-5/NO synthesis or otherwise release. I could be completely wrong, but I'll look into it. It would also explain why Mirapex can drastically increase libido while lowering acetylcholine, as lowered prolactin could lead to increased acetylcholine sensitivity.
Using SSRI's or opiates to treat PE can be effective. However, the reason that it "works" is because these drugs imitate or recreate the post sexual environment. During/before sex, Dopamine, Oxytocin, NE, sex hormones, acetylcholine and endorphins to a varying degree. After ejaculation there is a flood of serotonin, resulting in increased prolactin, a decrease in acetylcholine, a decrease in NE as well as a flood of oxytocin. Endogenous opiates are also released. Ever wonder why you feel sleepy, cuddly, relaxed and happy in general after sex? The above is why.
By taking those opiates and SSRI's etc, you are basically, to a degree, telling your body that you're done with sex. This decreases sexual potency, sensitivity and interest in general, it also makes if difficult for another "round" so to speak. It is however effective in treating PE.
However, by taking drugs that release Dopamine, sex hormones, acetylcholine, NE as well as a PDE-5 inhibitor we are giving ourselves an effective treatment for PE while maintaining sexual sensitivity/function as well as giving us the ability for multiple "rounds" if so desired not to mention a more intense desire.
Cocaine for example was found very quickly to be a potent aphrodisiac and many people provide anecdotal evidence of Cocaine's, and amphetamines ability to prolong sexual activity and desire. Most likely through the mechanisms described above.
