Zolpidem possible Cholinergic effects?

[Lightning-Nl]

L-enantiomer of Zopiclone is antinicotinic. That's why they've only approved Dextrozopiclone (Eszopiclone) here in the US for treatment of insomnia. It, apparently, has less anticholinergic actions.

@Ebola

There is evidence for it. Delirium, dry mouth, and other typical anticholinergic side-effects. I don't believe it to be to the extent of Zopiclone (if it does in fact exist, which I'm pretty damn sure it does) but it may still have anticholinergic actions. Also, I'm well aware of muscle relaxation of GABAergics. However, there are differences between typical GABAergic muscle relaxation, and neuromuscular blockers (antinicotinic drugs that are selective for muscle type nicotinic receptors). Zolpidem displays some effects typical of neuromuscular blockers. I don't remember what exactly, but that's what I read some time ago.

Also, I posted information earlier in this thread showing that Zolpidem actually induces a release of ACh. They compared these effects to Zopiclone and Diazepam. Zopiclone had similar actions on ACh release, while Diazepam did not. In fact, now that I think about it - that just makes the likelihood of Dopamine activity more likely - due to the Dopaminergic-Cholinergic relationship that is mediated by the neuropeptide Gherlin.

http://www.sciencedirect.com/science/article/pii/S0303720711001547

The gist of that study is - Dopamine receptor agonism causes immense downstream release of Acetylcholine. ACh receptor agonism causes immense downstream release of Dopamine. Gherlin mediates this response. Gherlin is the neuropeptide that is responsible for the feeling of pleasure you get from eating food.

 

[sekio]

Also, I posted information earlier in this thread showing that Zolpidem actually induces a release of ACh.

In one specific location in the rat brain, when zopiclone was delivered directly.... that is far from evidence it acts directly to block cholinergic responses. The authors concluded that it was evidence for subtypes of GABA-A receptors, did they not?

 

[Lightning-Nl]

In one specific location in the rat brain, when zopiclone was delivered directly.... that is far from evidence it acts directly to block cholinergic responses. The authors concluded that it was evidence for subtypes of GABA-A receptors, did they not?

Actually, there is conclusive evidence showing that both Zopiclone, Zolpidem, and Benzodiazepines directly block Nicotinic receptors. The study lists peripheral nicotinic-type receptors (ganglionic) in the study, so I guess that doesn't prove neuromuscular action. However, it does prove very active, centrally acting antinicotinic effects. Very interestingly enough - the same studies showed that both Z-drugs and Benzodiazepines also directly antagonize Glutaminergic N-Methyl-D-Aspartate receptors, and decreased excitability of the number 4, 6, 7, and 8 subtypes of the Metabotropic Glutamate receptors.

http://jpet.aspetjournals.org/content/302/2/612.full
http://www.sciencedirect.com/science/article/pii/S0014299905007235

With each study I read - the likelihood of increased Monoaminergic activity, due to Zopiclone and Zolpidem seems to become more and more possible. I am very intrigued. I'm also wondering why there is no studies clarifying this information.

 

[ebola?]

The first study you posted partially supports your hypothesis, though I'm having trouble comparing the magnitude of nicotinic and nmda antagonistic effects in comparison to zopiclone's (or desmethylzopiclone's) GABAnergic agonism. There are other issues: nicotinic antagonism has not been shown to cause muscarinic anticholinergic type delirium, so it can't explain that. Also, this effect is shared with conventional benzodiazepines, so it cannot explain zopiclone's unique effects. The second article does not support your hypotheses, instead pointing to zopiclone's increased selectivity among GABAnergic alpha subunits.

ebola

 

[skillet]

There is a really strange effect between it and hydroxzine...

It’s like a foogy dreamscape... Very foggy, loopy and floaty...

Yep, tried it last night with promethazine (75mg) and a 7.5mg zopiclone a few hours later. There's some serious potentiation there, I guess it would normally take around 3 zopiclone to get me z-drug 'tripping', and apart from tiredness that dose of promethazine is pretty subtle too.

 

[Lightning-Nl]

The first study you posted partially supports your hypothesis, though I'm having trouble comparing the magnitude of nicotinic and nmda antagonistic effects in comparison to zopiclone's (or desmethylzopiclone's) GABAnergic agonism. There are other issues: nicotinic antagonism has not been shown to cause muscarinic anticholinergic type delirium, so it can't explain that. Also, this effect is shared with conventional benzodiazepines, so it cannot explain zopiclone's unique effects. The second article does not support your hypotheses, instead pointing to zopiclone's increased selectivity among GABAnergic alpha subunits.

ebola

While all of that is true, you fail to recognize Zolpidem and Zopiclones acetylcholine releasing properties. Like I said above - when ACh agonism occurs, this causes a massive, downstream release of Dopamine that is mediated by the neruopeptide Gherlin. Same goes for DR agonism. When dopamine agonism occurs, it causes a huge downstream release of ACh, which again, is also mediated by the neuropeptide Gherlin. Lets put the antinicotinic and antiglutaminergic effects aside for a sec. Let's focus on how Zolpidem and Zopiclone may introduce such a large release of ACh. I'm sure there are many possibilities - but a couple things come to mind right off the bat (based on the typical effects of Z-Drugs).

Based on the profile of effects that Zolpidem causes, Zolpidem is either...

1. An Acetylcholinerstase Inhibitor
2. A Dopamine Agonist
3. A Dopamine Reuptake inhibitor
4. Some sort of ACh agonist (minus it's antinicotinic effects)
5. A Gherlin receptor agonist

As far as I'm concerned - the fact that Zolpidem releases ACh, proves that it has Dopaminergic effects. It may not be direct - but ACh agonism immediately causes Dopamine release. This likely contributes to the hallucinogenic properties of Zolpidem and Zopiclone. But there are also other factors present - such as the NMDA antagonism (which may be direct or indirect. The studies don't say. Either way it down regulates Glutaminergic activity) which also is likely to contribute to Zolpidem, Zopiclone's hallucinogenic effects. Maybe the Nicotinic antagonism causes the body to release more ACh in an attempt to upregulate nAChR? I don't know.

 

[ebola?]

While all of that is true, you fail to recognize Zolpidem and Zopiclones acetylcholine releasing properties.

I explicitly recognized it and asked a clarifying question about what's going on. You should look above to sekio's quip about the article, 'cause he had access to the full text that I did not. Most drugs exert minor activities that are not relevant at typical dosages, and the possible effect of zopiclone on cholinergic transmission could be an example of that. Besides, increased choliergic activity (well, that muscarinic) is the rough opposite of the cholinergic antagonism that causes delirium.

Either way it down regulates Glutaminergic activity

What? How so?

As far as I'm concerned - the fact that Zolpidem releases ACh, proves that it has Dopaminergic effects.

The brain is an incredibly complex, interconnected system. If we deem all downstream effects relevant, everything pretty much causes everything, which gets us nowhere in trying to understand how it works.

As far as I'm concerned - the fact that Zolpidem releases ACh, proves that it has Dopaminergic effects. It may not be direct - but ACh agonism immediately causes Dopamine release. This likely contributes to the hallucinogenic properties of Zolpidem and Zopiclone.

Why would this be? Hallucinogenesis is not associated with other far more potent and direct cholinergic agonists (muscarinic or nicotinic).

Maybe the Nicotinic antagonism causes the body to release more ACh in an attempt to upregulate nAChR? I don't know.

Increased release of a neurotransmitter is quite distinct from upregulation of its receptor, and the former often causes the opposite of the latter. It also seems more parsimonious that nicotinic antagonism would induce upregulation of nAch receptors, as this homeostatic mechanism is more direct.

ebola

 

[Lightning-Nl]

I explicitly recognized it and asked a clarifying question about what's going on. You should look above to sekio's quip about the article, 'cause he had access to the full text that I did not. Most drugs exert minor activities that are not relevant at typical dosages, and the possible effect of zopiclone on cholinergic transmission could be an example of that. Besides, increased choliergic activity (well, that muscarinic) is the rough opposite of the cholinergic antagonism that causes delirium.



What? How so?




The brain is an incredibly complex, interconnected system. If we deem all downstream effects relevant, everything pretty much causes everything, which gets us nowhere in trying to understand how it works.




Why would this be? Hallucinogenesis is not associated with other far more potent and direct cholinergic agonists (muscarinic or nicotinic).



Increased release of a neurotransmitter is quite distinct from upregulation of its receptor, and the former often causes the opposite of the latter. It also seems more parsimonious that nicotinic antagonism would induce upregulation of nAch receptors, as this homeostatic mechanism is more direct.

ebola

I think you completely misunderstood my post. I was listing possible MOA that Z-drugs may have in inducing their visual distorting effects. You have to keep in mind that all of this is speculation - I get that. I'm not trying to prove anything here, just openly discuss my thoughts. Also, you're totally wrong. You're right in the fact that the brain is the most complex thing we know of, and you're right in the fact that everything has downstream effects and that everything gets modulated. But what you fail to recognize is the fact that this isn't insignificant - it's everything!

Listing what downstream effects a drug has is entirely appropriate and it means everything! The brain isn't just a fist full of chemicals and receptors, it's far more complex than that. We know so little about the brain and the way it works that it's really impossible for anyone to really say with any certainty what exactly a drug "does do". We have to figure out what all of these downstream effects are because these downstream effects are what make us who we are and make us feel the way we do! So I completely disagree in that respect. Everything is important. Not just the main binding sites of some chemical.

With that being said, however, I was using knowledge of things that I already knew to just get a ballpark idea of what could cause these effects, based on what we already know about Z-drugs mechanism of action.

 

[sekio]

Listing what downstream effects a drug has is entirely appropriate and it means everything! The brain isn't just a fist full of chemicals and receptors, it's far more complex than that. We know so little about the brain and the way it works that it's really impossible for anyone to really say with any certainty what exactly a drug "does do". We have to figure out what all of these downstream effects are because these downstream effects are what make us who we are and make us feel the way we do! So I completely disagree in that respect. Everything is important. Not just the main binding sites of some chemical.

You can make some pretty convoluted leaps in judgement going by this logic. Certainly it is important to have a holistic view of a drug's effect, because of course humans aren't single cells plus a patch clamp setup, but at the same time it is vitally important to differentiate downstream, indirect effects from those caused directly, namely because empirically speaking a lot of the time the observed effects are different. The fact that neurons can be a lot more "targeted" in their releases of chemicals compared to small-molecule drugs diffusing throughout the whole brain means that assuming that drug X causes effect Y because of downstream activity at system Z may not always hold true.

For instance, THC is considered to be a CB1/2 receptor agonist. It is not, however, considered to be a dopamine receptor agonist, even though it functionally increases levels of dopamine some parts in the brain. The simple reason is because it lacks affinity and activity itself at dopamine receptors and the dopamine transporter. Without the presence of CB1/2 receptors on a cell THC will neither cause nor encourage dopamine release, it will have no effect.

These downstream effects caused by THC (and by extention cannabis) are also not your "typical" dopaminergic effects either, you rarely observe pseudoparkinsonian tics, urges to engage in risky behaviour (rages, hypersexuality, gambling), raised blood pressure, or intense vomiting, all hallmarks of dopamine receptor activation. Why is this the case? Because neurons only release chemicals into their local vicinity and hence only effect other nearby neurons; the "range" is limited by the speed of diffusion and the metabolic half life and is likely not farther than a centimetre. (Neurotransmitters that have a more "global" effect are probably better known as horomones.) So you could have CB1 activation causing dopamine release, but if the neurons releasing dopamine are not anywhere near the pituitary (such as in the NAcc) it will not activate D2 receptors responsible for prolactin secretion.[ref]

More importantly, in other cell types than the NAcc you might find cells that are activated by CB1 that do something entirely different, like modulate GABA for instance. This is why scientists report where in the brain they infuse compounds & draw samples from the CSF, and why they don't count "downstream" effects in with the "primary" effects.

We know so little about the brain and the way it works that it's really impossible for anyone to really say with any certainty what exactly a drug "does do".

We can sure make educated guesses though. And we do have tools today that are much more powerful than the old-fashioned bioassay. The most important thing is we can test our hypotheses much easier these days. You are also kidding yourself if you think we haven't advanced anywhere since the 1700s. Talk to a neurosurgeon sometime.

Based on the profile of effects that Zolpidem causes, Zolpidem is either...

Thought experiment: Why do other Z-drugs produce similar effects? Do they all share "the Swampfox Factor"? (I'm coining a term) Or can this be explained by subtype-selective GABA agonism, in those parts of the brain responsible for maintaining "the plot" - rendering your "internal world" so to speak?

 

[Lightning-Nl]

Thought experiment: Why do other Z-drugs produce similar effects? Do they all share "the Swampfox Factor"? (I'm coining a term) Or can this be explained by subtype-selective GABA agonism, in those parts of the brain responsible for maintaining "the plot" - rendering your "internal world" so to speak?

Haha, funny.

I guess I have a problem accepting that because the GABA system is entirely designed to stop excitation. But now I remember that specific subtypes do different things and in different areas. It's quite possible that being selective for a subtype could produce different GABAergic effects. Especially since different types of receptors are found on different cells. Yeah that's not impossible. In fact it's probable..........

I guess I should talk things out to myself before I post? But that's what I make these threads for....

 

[Lightning-Nl]

So I came up with another idea after doing something rather dangerous... After mixing a significant amount of Poppy Seed Tea with Temazepam, I experienced hallucinations that were nearly identical to that of Ambien. It was almost freaky to be honest. It honestly felt like I had just taken a huge dose of Ambien rather than PST and Temazepam. Now I don't want to claim anything as fact when the only proof I have is one subjective user report. However...

I believe we may be going about this in the wrong way. For the sake of discussion, let's say that Ambien doesn't produce it's 'hallucinogenic' effects through the GABA system. And since I already proposed the idea of D2 activity, let's rule that out as well. Maybe Ambien interacts with Kappa-Opioid or Sigma receptors?

That would explain the almost identical hallucinations I experienced last night with PST and Temazepam. But that can't be entirely it - because Temazepam is often shot with Heroin and I've never heard of people having Hallucinations from that combination. So maybe we should look at the combination of alkaloids in the Opium poppy plus the additive effects of Temazepam? Obviously the GABA system contributes in some way, however, it appears that effects somewhere else added on top of the gabanergic action is what likely makes the hallucinations

 

[ebola?]

How did this differ from the visions experienced from simply nodding on an opioid?

 

[Lightning-Nl]

How did this differ from the visions experienced from simply nodding on an opioid?

Mainly because I wasn't nodding. Not even close. They started right as I got up from my bed to go get a snack. If I was nodding - I'm pretty sure I would have just fallen asleep.

 

[sekio]

How would you explain some people's strangely paradoxical reactions to BZDs? There are cases of diazepam administration sending people into hallucinatory delerium. Here is one case although there was also a low dose of atropine, meperidine, & nitrous oxide. (not really making things easier for the poor guy)

Here is another case where low dose meperidine and diazepam caused delerium, disorientation, etc.

Here is a review of specifically sexual hallucinations while under anethesia (or perhaps just pervy doctors, hard to tell.). Apparently drugs like midazolam and propofol can cause dreamlike hallucinations.

Also, from personal communication, I know some people who can't take BZDs because it either effects their behaviour in a negative way (e.g. acting like a monkey), and some who have had one bad hallucinatory episode caused by benzos and then written them off.

This sort of paradoxical response to BZDs is known but seems to be most prominent in geriatrics and those who are genetically predisposed to it. It is not very common (one of the reviews suggests an incidence of a little more than 1 per cent) but it's not a novel action. It is also known that morphine can be almost hallucinogenic, esp. in combination with sigma agonist alkaloids from opium. Given the right dose and set/setting there is no reason you couldn't be stimulated yet all messed up on opioids.

 

[Lightning-Nl]

How would you explain some people's strangely paradoxical reactions to BZDs? There are cases of diazepam administration sending people into hallucinatory delerium.

Everyone is different. Some people are prone to paradoxical reactions to benzodiazepines, some are not. Tolerance also appears to play a contributing factor in these cases. For instance, low-doses of Amphetamine, even when applied directly to brain tissue, cause locomotor inhibition rather than locomotor stimulation after tolerance starts to develop. Whereas Low doses of Xanax tend to produce locomotor agitation rather than locomotor inhibition after some tolerance has been accumulated.

Both of the studies you listed, while interesting and relevant, can't be applied to benzodiazepines specifically because other drugs were obviously playing a part in the paradoxical reactions.

Also, Benzodiazepines and Zolpidem are two entirely different class of chemicals and are only moderately related in terms of pharmacology. I don't think that's a fair comparison.

This sort of paradoxical response to BZDs is known but seems to be most prominent in geriatrics and those who are genetically predisposed to it. It is not very common (one of the reviews suggests an incidence of a little more than 1 per cent) but it's not a novel action. It is also known that morphine can be almost hallucinogenic, esp. in combination with sigma agonist alkaloids from opium. Given the right dose and set/setting there is no reason you couldn't be stimulated yet all messed up on opioids.

I don't disagree with that. Opioids are well known for their Dopaminergic effects. However, GABA suppresses dopamine release. However, the hallucinations weren't present until the GABA modulator was introduced. That indicates that the combination of gabanergic action and some other, unspecified action is what causes the hallucinations.

 

[ebola?]

Also, Benzodiazepines and Zolpidem are two entirely different class of chemicals and are only moderately related in terms of pharmacology.

Zolpidem is extremely similar to benzodiazapines, albeit more selective for the alpha-1 subunit GABAA receptor. In fact, 'z-drugs' are more similar to benzodiazepines than they are to any other class of psychoactive compound.

ebola

 

[Lightning-Nl]

Zolpidem is extremely similar to benzodiazapines, albeit more selective for the alpha-1 subunit GABAA receptor. In fact, 'z-drugs' are more similar to benzodiazepines than they are to any other class of psychoactive compound.

ebola

Wow really? I had no idea!

I was talking about molecular structure, and pharmacology. Yes, z-drugs are pretty similar to benzos in pharmacology, but their molecular structure isn't. Don't you think that it just might be possible that Zolpidem's unique molecular structure (especially in relation to other sedatives) could have action else where? Isn't that the least bit possible?

 

[sekio]

The way I've always seen it is, zolpidem is selective for some site on some subtype of GABA-A that other benzos only hit incidentally in others. (and is not its "primary" site, the alpha1- subunit). Zopiclone does not produce all of its action through alpha1 subunit agonism, as demonstrated by studies on knockout mice.
The discriminative stimulus of zolpidem is similar to that of most benzos, too. But at the same time if it does have action at other sites typical of hallucinogenic action, it's not been observed so far. It also seems that it produces hallucinogenic effects primarily in cases where its blood concentration can be "artificially" elevated above theraputic levels - e.g. concomittant use of drugs which compete for plasma binding like SSRIs, the elderly, & women.

Here's perhaps a better reference for my point, a case of an elderly man who had hallucinatory cats appear upon taking temazepam, but not on a low dose of zopiclone.


It would not surprise me at all if there was some specific subtype or receptor dimer of GABA-A that causes dreamlike hallucinations.

It could also be related to its pharmacokinetics. Drugs like triazolam and other ultra fast acting hypnotics have a bad record of inducing sleep walking. This paper from Med Hypotheses suggests part of zolpidem's strange behaviors come from its ability to rapidly desensitize GABA-A receptors before the body can compensate.

 

[Lightning-Nl]

The way I've always seen it is, zolpidem is selective for some site on some subtype of GABA-A that other benzos only hit incidentally in others. (and is not its "primary" site, the alpha1- subunit). Zopiclone does not produce all of its action through alpha1 subunit agonism, as demonstrated by studies on knockout mice.
The discriminative stimulus of zolpidem is similar to that of most benzos, too. But at the same time if it does have action at other sites typical of hallucinogenic action, it's not been observed so far. It also seems that it produces hallucinogenic effects primarily in cases where its blood concentration can be "artificially" elevated above theraputic levels - e.g. concomittant use of drugs which compete for plasma binding like SSRIs, the elderly, & women.

Here's perhaps a better reference for my point, a case of an elderly man who had hallucinatory cats appear upon taking temazepam, but not on a low dose of zopiclone.


It would not surprise me at all if there was some specific subtype or receptor dimer of GABA-A that causes dreamlike hallucinations.

It could also be related to its pharmacokinetics. Drugs like triazolam and other ultra fast acting hypnotics have a bad record of inducing sleep walking. This paper from Med Hypotheses suggests part of zolpidem's strange behaviors come from its ability to rapidly desensitize GABA-A receptors before the body can compensate.

If the alpha-1 sub unit IS that subtype, what would be it's purpose? It seems paradoxical for evolution to design a system entirely mediated to inhibition, and then, evolve to have a subtype that indirectly causes stimulation, doesn't it?

The only purpose I can think of is; maybe alpha-1 is responsible for triggering REM sleep? I know that's a long shot, but it's a possible explanation to its behavior - wouldn't you say? Maybe alpha-1 is primarily located on Noradrenergic, Glutamatergic, Cholinergic, and Serotonergic associated neurons and by slowing down their firing, this triggers REM sleep behavior but fails to produce nerve muscle inhibition? This study supports that hypothesis.

http://m.jneurosci.org/content/32/29/9785.long

However, it also indicates that GABA-B and Glycine receptor activity play a major part in REM sleep. Maybe the lack of activation of GABA-B activity still allows for sufficent potassium invoked motor behavior and therefore, there is still sufficent excitation to produce movement? Just an idea...