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Zolpidem Receptor Affinity?

SpunkySkunk347

SpunkySkunk347

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I know zolpidem is an agonist for nearly all GABA subtypes, or atleast a partial agonist.

I also heard somewhere that zolpidem also has affinity for 5-HT2a and other 5-HT2 suptypes.
This would explain the reported similar effects it has with LSD.
Maybe what I heard was misinformation or maybe I just imagined it.

Does anybody know?
 
No 5-HT receptor affinity. There are certain GABA receptors that are expressed in the visual cortex which are affected by some GABAergic drugs, namely muscimol, gaboxadol, and zolpidem.
 
Zolpidem is a1-selective, it's not a sloppy bzd-gaba-agonist.

But I've never seen a study that said there's no 5HT affinity, and until I do, I sincerely doubt it's has to do with local GABA receptors the way it does with muscimol.

We also don't know what you're saying about Gaboxadol, we only know that drug users liked it at 3x the daily max dose, that's not the same as hallucinations.

AFAIK, we don't know that to be true for Zolpidem either.

With the structural similarity's to the tryptamine (and knowing that the indole core can be played around with quite a bit to yield an active psychedelic- ie: swapping the nitrogen for an oxygen), I wouldn't rule anything out without actually seeing a paper that said that it didn't have any 5HT2a affinity.

If anyone knows of a paper that says it doesn't, I'd love to see it, as it'd answer a lot of questions for me, but otherwise, it just seems awfully premature to say that it's not. The structure certainly says it may be.
 
All papers that I saw state a GABAA-selectivity. Some indirect interaction with serotonergic systems is suggested but for sure no direct action at any 5HT-receptor.
 
I asked this before and got no definite answers, so I'll ask again in hopes of getting more info.

Does Zolpidem have any known NMDA-antagonist activity? Every time I take it, I feel a VERY definite Dissociative "signature" that is particularly reminiscent of PCP.
 
Jamshyd,I was just about to post the same,last year on my trip back from Cuba I got a Zolpidem from a friend and after a few minutes after taking it I thought I have taken a dissociative.
 
^ that's an interesting theory.

however, does anyone actually have a paper saying no 5HT2a affinity for zolpidem? Why do we accept one thing as truth with no research, but reject another for a lack thereof?
 
Evidence indicates that the GABAergic regulation of 5-HT neurones in the median raphe nucleus (MRN) may be involved in sleep and waking. Thus, MRN 5-HT neurones receive GABAergic inputs from sleep-active neurons in the ventrolateral preoptic nucleus (Sherin et al. 1998). Furthermore, GABA receptor activation of MRN 5-HT neurones induces hippocampal theta activity, which is associated with rapid eye movement sleep (Varga et al. 2002). However, relatively little is known about GABAA receptor control of MRN 5-HT neurones and the effects of Z hypnotics, which act at the GABAA receptor are unknown.
In vitro electrophysiology was used in the present study to a) examine the regulation of the firing of MRN 5-HT neurones by GABAA receptors b) examine the effects of a Z hypnotic on the GABAA receptor inhibition of 5-HT neuronal activity. Brains from male Lister Hooded rats were used. Slices containing the MRN were perfused with artifical cerebrospinal fluid containing 30 μM noradrenaline (NA) to evoke firing in 5-HT neurones. Drugs were applied by addition to the perfusate: 5-HT and the GABAA receptor agonist 4,5,6,7 tetra*hydr*isoxazolo[5,4-c]*pyridin-3-ol (THIP) were applied for 2 min, the GABAA antagonist bicuculline and the Z hypnotic zolpidem were applied before and during reapplication of THIP.
Data shown are mean ± SEM. Neurones in the MRN which fired slowly (1.1±0.5 Hz, n = 42) and regularly in the presence of 30 μM NA and were inhibited by 5-HT (10–50 μM) were presumed to be 5-HT neurones. THIP (10–50 μM) inhibited the firing of all neurones tested. The inhibitory responses to THIP (10–50 μM) were attenuated by bicuculline (50 μM) (n = 9) and were concentration-dependent (n = 7). Zolpidem (200 nM) alone had no effect on the basal firing rate of the MRN 5-HT neurones (n = 8, p = 0.4, paired t-test). However, zolpidem (200 nM) did enhance the inhibitory response to a submaximal concentration of THIP (10–25 μM) (mean enhancement of THIP response: 69.8±20.4% (n = 8), p < 0.01, t-test). The potentiation of the response to THIP increased with increasing concentrations of zolpidem (mean enhancement of THIP response: 199.8±36.7% with 1 μM zolpidem (n = 5), 350.0±112.0% with 5 μM zolpidem (n = 4)).
The data indicate that GABAA receptors inhibit 5-HT neuronal firing in the MRN and that the Z hypnotic zolpidem enhances this inhibition. These data may have implications for sleep disorders.
http://ex2.excerptamedica.com/05ecn...2005 12:00-14:00 &abstrnbr=P.1.065
Click to expand...

Doesn't 4-HO-DMT inhibit activity in the MRN/NCS?
 
Excellent find negrogesic!

By the way, sorry for the mistake, I didn't know zolpidem was a1 selective
 
Quoting the posted abstract:
Evidence indicates that the GABAergic regulation of 5-HT neurones in the median raphe nucleus (MRN) may be involved in sleep and waking.
Click to expand...
As I said above: No direct action (agonist or antagonistic) at a 5HT-receptor but rather (if at all) indirect action, like here, of a neuron on another neuron.
So, one could postulate 5HT-modulating actions rather than agonistic ones.

Peace! Murphy
 
Ham-milton said:
i honestly don't know what to take from that study
Click to expand...

5HT2A receptors have either an excitatory or inhibitory effect depending which part of the brain they are expressed in, but what the cited study is saying is that in the particular parts of the brain they looked at where neurons bearing inhibitory 5HT2A receptors are expressed, there are also GABA-A receptors bearing α1 subunits on the same neurons.

GABA-A receptors of course have an inhibitory effect, so when they are activated on neurons which also have an inhibitory response to 5HT2A activation, this results in double inhibition of neuronal activity, hence the GABA-A agonists in this case will be expected to enhance 5HT2A mediated hallucinogenic activity.

This is not that surprising as the two GABA agonists they used in the study are both ones that are known to have hallucinogenic effects (THIP is better known now days as gaboxadol) but it provides an interesting hint at the mechanism by which this hallucinogenic effect may be produced.
 
Ah ha, that makes sense.

Sort of.

That seems to say that Zolpidem would strongly potentiate a 5HT2a hallucinogen. But in the absense of a 5HT2a agonist?

Now: Does anyone have any paper that looked at zolpidem's 5HT2a affinity?!?! I guess even if it were very low, then perhaps it's binding in these very selective regions just enough to cause the hallucinations? I don't know that I buy the GABA-C thing, especially in this case; muscimol and gaboxadol, sure, but not zolpidem. Muscimol produces really weird almost-visuals, and I don't think we have any 'proof' that gaboxadol produced visual effects that led to it's discontinuation (or do we?), but it seems likely enough- but zolpidem produces very different visuals, that are indistinguishable 5HT2a agonists.

so again: why are we accepting that there's no 5HT2a affinity? And why are we accepting that gaboxadol produces visuals? I have seen a paper that says either of those things are true.
 
Well there doesn't need to be an exogenous 5HT2A agonist if the pathway is potentiated strongly enough, because remember that there is always endogenous 5HT around to stimulate 5HT2A receptors, and if adding certain kinds of GABA agonist stimulates the hallucinogenic 5HT2A pathway while leaving other serotonergic effects unaltered, then this may well produce hallucinogenic effects merely from normal levels of 5HT2A activation.

This evidence pretty much explains the hallucinogenic effects of zolpidem without needing any 5HT2A activity for zolpidem itself. Bear in mind that zopiclone and zaleplon also have the same kind of hallucinogenic effect as zolpidem, and they certainly don't share its vague structural resemblence to DMT.

Also I'm pretty sure there is evidence that gaboxadol produced hallucinogenic effects, certainly the official press release said it was pulled because of neurological side effects, and I read earlier that the neurological side effects in question were indeed hallucinogenic in nature, its just that they weren't really that significant in their earlier trials at therapeutic doses, only once they upped the dose to simulate "abusive" use of the drug did the effects become prominant enough to be of concern. I'd say the company just got cold feet about putting out a sleeping pill that might have abuse potential and hallucinogenic side effects, because the whole selling point of gaboxadol was that it was supposed to be an advance over the Z-drugs, so finding that it has exactly the same shortcomings as the Z-drugs means that it is no longer an advance and lost any advantage that might have given it a commercial edge.
 
I can't believe ambien is still legal. A simple google search for "ambien hallucination" will result in hundreds of people complaining that they took ambien to get to sleep and started freaking out when everything in their room became alive.

Its really an amazing drug. Last night I had a conversation with my bedroom door, it was morphing like crazy and faces kept appearing in it. Nothing was a definite shape, and my brains sense of geometry was completely compromised.

The visuals are so reminiscent of mushrooms and LSD, I can't doubt for a second that there is atleast some indirect action with 5-HT2a receptors.
 
Jamshyd said:
Does Zolpidem have any known NMDA-antagonist activity? Every time I take it, I feel a VERY definite Dissociative "signature" that is particularly reminiscent of PCP.
Click to expand...

Unlikely. However, due to the recent discovery of racemic Zopiclone's potent anticholinergic effects, it would stand to reason that other drugs of the Imidazopyridine group would also be antimuscarinic drugs. Therefore, I believe it's highly likely that Zolpidem also possess anticholinergic effects.
 
I take zolpidem ER 12.5 mg regularly, and would love to have a better pharmacological understanding of why this drug is so "weird" for lack of a better term. I've never doubled up a dose because of a suspicious feeling that it would be an insta-blackout, as far as remembering the experience is concerned. I definitely notice the inability to form short-term memories on larger doses of benzos, but Ambien feels different somehow, more of a dreamless blackout, or more likely, a wacky, vibrant dream that you can't remember because of the blackout effect. I was given IV diazepam/midazolam once as a child for an upper GI procedure, the midaz "so I wouldn't remember what happened" (I did remember, it was hugely traumatic). Ambien seems like a drug out of Memento. Maybe they should look into Ambien as a drug to prevent anesthesia awareness.

My ex-shrink didn't like to prescribe Ambien at all because of the bizarre reports her patients would return with. E.g., one of her patients was surprised by the doorbell ringing one afternoon, and doubly surprised to find that she had apparently ordered a many-thousands-of-dollars purebred cat online from a breeder one evening online in an Ambien haze. They do not take returns. Oh, and Zinger! She hates cats.
 
What size doses are you taking, skunk?

SpunkySkunk347 said:
I can't believe ambien is still legal. A simple google search for "ambien hallucination" will result in hundreds of people complaining that they took ambien to get to sleep and started freaking out when everything in their room became alive.

Its really an amazing drug. Last night I had a conversation with my bedroom door, it was morphing like crazy and faces kept appearing in it. Nothing was a definite shape, and my brains sense of geometry was completely compromised.

The visuals are so reminiscent of mushrooms and LSD, I can't doubt for a second that there is atleast some indirect action with 5-HT2a receptors.
Click to expand...
 
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