5-HT Related Pharmacology Question

[Diloadid]

Didn't know where to really post this, so here goes.

In trying to better understand the way things work and doing some background research on said chemicals. I've come to ask a question about agonist and antagonist for specific 5-HT receptors.

To simplify this >

The 5-HT2b Receptor

MDMA is an agonist for this receptor. BZP is an antagonist for this receptor, and a few other 5-HT receptors I think.

I know that MDMA is also a DA agonist, but unsure about BZP (but I do know that it has some affinity for DA).

My question is ; Would the serotonin effects of MDMA be nullified, diminished, or possibly replaced if you were to dose BZP shortly after?

If not, what would happen where one is an agonist and the other antagonist?

This is hypothetical of course.

 

[Ryan D.]

It seems likely that the use of 5 HT antagonists would indeed diminish the effects of MDMA somewhat, but i imagine the effects of MDMA would still be quite significant.
MDMA acts as a potent releasing agent and re-uptake inhibitor for serotonin, dopamine and norephinephrine (exerting its greatest effect on serotonin levels) at least i think so.

 

[Diloadid]

Interesting.

This question would be easier answered if I directly understood the pharmacology of BZP. I am finding mixed information that is suggesting it acts/mimics as a releasing agent and/or reuptake inhibitor for serotonin.

 

[Tommyboy]

I'll try this over in ADD. I'm not sure if it has enough big words for that forum or if it's complicated enough, but we'll see what they think over there.

Homeless --> ADD

 

[AlphaMethylPhenyl]

If BZP is indeed an antagonist for a few receptors which MDMA agonizes, then expect diminished effects from a combination of the two. You should still be able to feel the MDMA and possibly even roll if the dosage is high enough, but MDMA is a substance of "questionable safety" so I wouldn't up the dose due to this.

 

[sekio]

bzp is probably a low enough affinity substrate for the 5-ht receptors that, as long as you weren't taking gram doses, there wouldnt be much loss of effects from the mdma
but generally combining mdma and piperazines is asking for a bad time

 

[Incunabula]

To simplify this >

The 5-HT2b Receptor

MDMA is an agonist for this receptor. BZP is an antagonist for this receptor, and a few other 5-HT receptors I think.

I don't think that the agonism/antagonism these 2 compounds have on the 5-HT2b Receptor adds much to their respective effects. So yeah, BZP might change how you roll on MDMA a little bit, but you would also risk serotonin syndrome.

I might be completely wrong though.

 

[chaos_destroy]

5-ht2B receptor activity is essential in MDMA's action so depending on how strong BZP is at antagonizing this receptor it may very well limit the effects of MDMA.


Doly, S., J. Bertran-Gonzalez, et al. (2009). "Role of serotonin via 5-HT2B receptors in the reinforcing effects of MDMA in mice." PLoS One 4(11): e7952.

Doly, S., E. Valjent, et al. (2008). "Serotonin 5-HT2B receptors are required for 3,4-methylenedioxymethamphetamine-induced hyperlocomotion and 5-HT release in vivo and in vitro." J Neurosci 28(11): 2933-2940.

 

[Diloadid]

bzp is probably a low enough affinity substrate for the 5-ht receptors that, as long as you weren't taking gram doses, there wouldnt be much loss of effects from the mdma
but generally combining mdma and piperazines is asking for a bad time

Ahh. See I was just trying to make sense of the fact that both act on the same receptor, was just curious what the overall outcome would be where one agonizes and the other antagonizes. I really would never plan on taking any piperazine. Just used those two as an example because it was the easiest two to point out.

So as long as you weren't taking a massive dose of BZP, the MDMA would probably still be noticeable?

Sorry for asking silly questions. Again hypothetically, would there be a level that you could dose the BZP to completely negate the actions of MDMA for agonizing that receptor? And this might be a really really dumb question, but between the two which has a more noticeable action on the 5-ht2b receptor (given a general recreational dose)? And if at all possible if you know of any semi-dumbed down text that offers information on agonist and antagonist it would cool. Because Google Scholar and Wikipedia only garnish so much information (that I can understand).

 

[endotropic]

Ahh. See I was just trying to make sense of the fact that both act on the same receptor, was just curious what the overall outcome would be where one agonizes and the other antagonizes. I really would never plan on taking any piperazine. Just used those two as an example because it was the easiest two to point out.

So as long as you weren't taking a massive dose of BZP, the MDMA would probably still be noticeable?

No amount of 5HT2b antagonism will completely block the effects of MDMA. The 5HT1a and 5HT2a receptor are also required for MDMA effects, and the other 11 serotonin receptors probably can't be ignored either. If you had some drug that antagonized all 14 serotonin receptors THEN maybe you'd block MDMA effects entirely.

Sorry for asking silly questions. Again hypothetically, would there be a level that you could dose the BZP to completely negate the actions of MDMA for agonizing that receptor? And this might be a really really dumb question, but between the two which has a more noticeable action on the 5-ht2b receptor (given a general recreational dose)? And if at all possible if you know of any semi-dumbed down text that offers information on agonist and antagonist it would cool. Because Google Scholar and Wikipedia only garnish so much information (that I can understand).

Yes there should be a dose where BZP completely antagonizes the action of MDMA at 5HT2b, whether someone could actually dose this much without croaking is the real question. Interesting to note that by antagonizing 5HT2b the cardiotoxic effects of MDMA would be reduced, but by adding to the serotonin load the neurotoxic effects would probably be increased.

In general you feel the effects of an agonist at a given receptor more than you feel an antagonist, but it's really a case by case basis (see NMDA receptor antagonists for an exception). Considering there aren't really any selective 5HT2b antagonists in use it's a bit hard to say for sure, but looking at the studies chaos linked I would guess MDMA's effects on 5HT2b are more noticeable/recreational.

As far as general information on agonists/antagonists and pharmacology in general, try here: http://www.bluelight.ru/vb/threads/166687-Erowid-BlueLight-Neuropharmacology-Text

 

[Incunabula]

Ahh. See I was just trying to make sense of the fact that both act on the same receptor, was just curious what the overall outcome would be where one agonizes and the other antagonizes. I really would never plan on taking any piperazine. Just used those two as an example because it was the easiest two to point out.

So as long as you weren't taking a massive dose of BZP, the MDMA would probably still be noticeable?

Sorry for asking silly questions. Again hypothetically, would there be a level that you could dose the BZP to completely negate the actions of MDMA for agonizing that receptor? And this might be a really really dumb question, but between the two which has a more noticeable action on the 5-ht2b receptor (given a general recreational dose)? And if at all possible if you know of any semi-dumbed down text that offers information on agonist and antagonist it would cool. Because Google Scholar and Wikipedia only garnish so much information (that I can understand).

I think that a better hypothetical example could be antipsycotics and serotonergic psychedelics.

Most psychedelics that are agonists for the 5-HT2A serotonin receptors have their effects completely or partly negated by antipsychotics that are antagonists at the 5-HT2A receptor. For example, people sometimes use Seroquel (Quetiapine) to abort bad trips. Supposedly very effective.

I don't think that the agonism/antagonism these 2 compounds have on the 5-HT2b Receptor adds much to their respective effects. So yeah, BZP might change how you roll on MDMA a little bit, but you would also risk serotonin syndrome.

I might be completely wrong though.

What an uninformed load of crap. It was early in the morning and I was kind of trying to convey the same point that Sekio did, so i must'nt have seen his post. lol.

 

[Diloadid]

Ahh, thanks for all the information everybody. It all seems very understandable now.

The comparison with the 5ht-2a receptor and anti-psychotics really gave me a good mental understanding.

It also makes sense that if you had a chemical that antagonized all 14 receptors, you could negate the serotonin-aspects of MDMA.

It is silly in thought to question a substance that greatly antagonized all 14 receptors in negating the serotonin-effects of MDMA entirely.

I guess if you negated the serotonin release, and only had dopamine and norepinephrine release the resulting effects would be closer to methamphetamine or amphetamine. I dunno why it bothers me to want to know this. Just curiosity.

 

[chaos_destroy]

Without activation of 5-ht2b by MDMA directly, MDMA causes no serotonin or dopamine release. Probably more than anything blocking this receptor will kill the roll.

 

[endotropic]

Without activation of 5-ht2b by MDMA directly, MDMA causes no serotonin or dopamine release. Probably more than anything blocking this receptor will kill the roll.

Wait what? This doesn't make any sense to me. MDMA acts directly on SERT and VMAT2 to cause serotonin release, how does blocking 5HT2b stop this process?

Edit: Well that second paper you linked is pretty convincing, I guess disregard everything I wrote above. I still don't understand how this is occurring but blocking 5HT2b completely blocks MDMA induced serotonin release. Has anyone tried this in humans?

 

[MollyFein74]

Have nevr heard that serotonin release is blocked by blocking 5HT2b... Maybe some of the effects of MDMA are diminished by blocking 5ht2b ie the physcedelic effects such as music enhancement, visual enhancement/hallucinations and physical feeling/physical euphoria.