What does 5-HT2a antagonism do? (more specifically, for depression.)

[JackiesBabyy]

5HT2A receptors are overactive in melancholic depression and can help that, antagonism wont help atypical depression. Agonism is beneficial for atypical depression and ocd.

Yes, we know that. All of the sources say 5-HT2a receptors are involved in depression, but nowhere can I find something saying what aspect of depression is linked to overactive 5-HT2a receptors. I have no clue seeing as psychedelics activate 5-HT2a and being depressed shares 0 similarities with a psychedelic trip. (except for psychotic depression, but that's not what we're talking about)

 

[endotropic]

Yes, we know that. All of the sources say 5-HT2a receptors are involved in depression, but nowhere can I find something saying what aspect of depression is linked to overactive 5-HT2a receptors. I have no clue seeing as psychedelics activate 5-HT2a and being depressed shares 0 similarities with a psychedelic trip. (except for psychotic depression, but that's not what we're talking about)

This doesn't directly answer your question, but keep in mind that serotonin activating the 5-HT2a receptor causes a much different subjective effect than a psychedelic activating the 5-HT2a receptor. It's certainly possible to have overactive 5-HT2a receptors without any psychedelia.

 

[JackiesBabyy]

This doesn't directly answer your question, but keep in mind that serotonin activating the 5-HT2a receptor causes a much different subjective effect than a psychedelic activating the 5-HT2a receptor. It's certainly possible to have overactive 5-HT2a receptors without any psychedelia.

And I wonder how people get euphoria from 5-HT2a agonists most of the time. I've read LSD has action at the dopamine receptors, maybe that's why? I don't think any psychedelics are totally selective to 5-HT2a.

 

[MeDieViL]

And I wonder how people get euphoria from 5-HT2a agonists most of the time. I've read LSD has action at the dopamine receptors, maybe that's why? I don't think any psychedelics are totally selective to 5-HT2a.

They act on alot more of receptors, that said da is more associated with wanting, mu is most likely what causes reward.

 

[MeDieViL]

Yes, we know that. All of the sources say 5-HT2a receptors are involved in depression, but nowhere can I find something saying what aspect of depression is linked to overactive 5-HT2a receptors. I have no clue seeing as psychedelics activate 5-HT2a and being depressed shares 0 similarities with a psychedelic trip. (except for psychotic depression, but that's not what we're talking about)

The diff btw melancholic and atypical might provide clue's, prob more downstream involved, antagonists dont cause releif straight away

 

[JackiesBabyy]

The diff btw melancholic and atypical might provide clue's, prob more downstream involved, antagonists dont cause releif straight away

Atypical depression is far more likely to be helped by MAOIs. That on top of the fact that it causes excessive sleeping, excessive eating, and hypersensitivity to rejection(caused by losing confidence in yourself), suggests Atypical Depression is primarily a dopamine related problem. MAOIs effect NE and 5-HT too, but what separates MAOIs from TCAs is that they cause a large increase in dopamine in addition to how most TCAs cause a large increase in NE/5-HT.

During my AD episodes, stimulants (d-amphetamine, to be specific) was an instant cure and made everything totally better temporarily, while I've been told by people with melancholic(insomnia, anorexia) depression that stimulants either don't help or make it worse by causing anxiety with no mood lift.

 

[ungelesene_bettlek]

These paper's don't say anything about MDMA's ability to cause "Magic" because they weren't written by bluelighters, but they do explain the different mechanisms of MDMA and its enantiomers:

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") and its stereoisomers as reinforcers in rhesus monkeys: serotonergic involvement.
http://www.ncbi.nlm.nih.gov/pubmed/12073162

Pharmacological characterization of the effects of 3,4-methylenedioxymethamphetamine ("ecstasy") and its enantiomers on lethality, core temperature, and locomotor activity in singly housed and crowded mice.
http://www.ncbi.nlm.nih.gov/pubmed/12563544

Fantegrossi has a whole series of papers comparing MDMA and its enantiomers, look him up if you're still interested.

it would be great if you could perhaps give the short version in two sentences, please?

most important for MDMA's action is well-balanced monoamine release, correct? AFAIK the S-isomer is more potent in that apartment. 5HT1A agonism (and oxytocine release triggered by it) seems to also play some role. I guess the R-isomer then contributes this part, since generally the R-isomers are the more potent 5HT-agonists. what else plays a role? 5HT2A agonism? R-MDA generated by metabolism could contribute that, but I always thought that was quite irrelevant at regular dosage levels?

 

[JackiesBabyy]

it would be great if you could perhaps give the short version in two sentences, please?

most important for MDMA's action is well-balanced monoamine release, correct? AFAIK the S-isomer is more potent in that apartment. 5HT1A agonism (and oxytocine release triggered by it) seems to also play some role. I guess the R-isomer then contributes this part, since generally the R-isomers are the more potent 5HT-agonists. what else plays a role? 5HT2A agonism? R-MDA generated by metabolism could contribute that, but I always thought that was quite irrelevant at regular dosage levels?

I don't think MDMA binds to any receptor, just releases serotonin to bind to all of the receptors?

 

[sekio]

MDMA does have affinity for some serotonin receptors, 5ht2b notably. I think the release of serotonin is responsible for 5ht1a activation though.

 

[JackiesBabyy]

Never heard anything about 5-ht2b's effects, but another thing to take in to account, 5-ht2c agonists suppress dopamine (and one of SSRI's mechanisms is killing 5-ht2c receptors by downregulation). Not sure if it's enough to play a role in the effects.

 

[ungelesene_bettlek]

MDMA does have affinity for some serotonin receptors, 5ht2b notably.

does it act as agonist or antagonist there? so how much does this contribute to the overall action? is it reasonable to assume that the 5HT2B receptor affinity can be contributed to the R enantiomer?

I think the release of serotonin is responsible for 5ht1a activation though.

I found the following paper regarding this question: http://www.ncbi.nlm.nih.gov/pubmed/18635693

obviously, the hypothesis regarding the oxytocin release due to direct 5HT1A agonism comes from animal models and could not be verified in this study with humans.

so the question remains: what part of the MDMA "magic" is contributed by the R enantiomer?

to contribute something to the actual topic as well: trazodone is marked as antidepressant, and one of its main actions is 5HT2A antagonism as well (besides that it also antagonizes 5HT2B and 5HT2C, is a partial agonist at 5HT1A and a SRI).

 

[JackiesBabyy]

Source? It's the first I've heard of that. Or do you mean 5-ht1a?

I'm curious about any evidence that blocking 5-ht2a causes increased serotonin levels (that Wizzle also suggested) as well. It sounds reasonable but I can't think of a good way to phrase it for a search. All I could really find is this:





Really? Why don't psychedelics usually cause sexual problems?

1. I'm pretty sure 5-ht1a is the autoreceptor, not 5-ht2a
2. About the sexual problems, I've been told that the serotonin activating 5-HT2a may not have the same effect as an agonist at 5-HT2a.

 

[JackiesBabyy]

does it act as agonist or antagonist there? so how much does this contribute to the overall action? is it reasonable to assume that the 5HT2B receptor affinity can be contributed to the R enantiomer?


I found the following paper regarding this question: http://www.ncbi.nlm.nih.gov/pubmed/18635693

obviously, the hypothesis regarding the oxytocin release due to direct 5HT1A agonism comes from animal models and could not be verified in this study with humans.

so the question remains: what part of the MDMA "magic" is contributed by the R enantiomer?

to contribute something to the actual topic as well: trazodone is marked as antidepressant, and one of its main actions is 5HT2A antagonism as well (besides that it also antagonizes 5HT2B and 5HT2C, is a partial agonist at 5HT1A and a SRI).

All I can find as far as 5-HT2b cns effects of being blocked is that it's anxiolytic. Same with activation of 5-ht1a yet trazodone really isn't anxiolytic at all to me. I've read on here it's sedation is because of being an alpha 1 antagonist, yet other sources say it's mostly the 5-HT2a antagonism.

 

[AlphaMethylPhenyl]

Its reasonably both of them. Psychedelics are known for being difficult or impossible to sleep on.

Trazodone has a complicated, muddling pharmacology so it wouldn't be right to draw pharmacological conclusions based on it being anxiolytic or not.

Also though an antagonist at the site of which this thread is about may have an antidepressant effect its not sanctioned as such by governments or corporations. There was an article in a popular newspaper a while ago about doctors being punished for giving out anti-psychotics to treat depression, part of the mechanism being 5-HT2a antagonism.

 

[JackiesBabyy]

Its reasonably both of them. Psychedelics are known for being difficult or impossible to sleep on.

Trazodone has a complicated, muddling pharmacology so it wouldn't be right to draw pharmacological conclusions based on it being anxiolytic or not.

Also though an antagonist at the site of which this thread is about may have an antidepressant effect its not sanctioned as such by governments or corporations. There was an article in a popular newspaper a while ago about doctors being punished for giving out anti-psychotics to treat depression, part of the mechanism being 5-HT2a antagonism.

Even before I learned about pharmacology I always looked up whatever a pill was before I took it, you're dumb if you just take a pill you know nothing about and never heard of just because a doctor handed it to you. Antipsychotics are one of the few drug classes I'd never put in myself unless forced. Just, no.

 

[MeDieViL]

Using ap's for depression is retarded, mirtazepine or cyproheptadine can be usefull adjuncts for sero antagonism, lack of selectivity is a problem tough as antagonism of other receptors can counter the positives of 5HT2A antagonism.

Lisuride is the only 5HT2A agonist that activates the receptor as serotonin.

 

[skillet]

does it act as agonist or antagonist there? so how much does this contribute to the overall action? is it reasonable to assume that the 5HT2B receptor affinity can be contributed to the R enantiomer?

It's a partial agonist. It contributes a lot, according to this!:

Administration of MDMA increased extracellular 5-HT concentration in WT mice ~80-fold within 70 min in both the NAcc (Fig. 2a) and the VTA (Fig. 2d). In 5-HT2B -/- mice as well as in mice pretreated with
RS127445, MDMA caused no increase in extracellular 5-HT concentration in the NAcc (Fig. 2b,c) and the VTA (Fig. 2e,f ). In WT mice, MDMA caused an 80-fold increase in extracellular DA levels in the NAcc within 50 min (Fig. 3a). However, in RS127445-treated (Fig. 3b) or 5-HT2B -/- mice (Fig. 3c), MDMA caused no increase in extracellular DA concentration in the NAcc.

 

[JackiesBabyy]

Using ap's for depression is retarded, mirtazepine or cyproheptadine can be usefull adjuncts for sero antagonism, lack of selectivity is a problem tough as antagonism of other receptors can counter the positives of 5HT2A antagonism.

Lisuride is the only 5HT2A agonist that activates the receptor as serotonin.

5-HT2a agonists include every psychedelic drug that isn't dissociative/deliriant. But Trazodone is primarily a 5-HT2a antagonist without being an antipsychotic, there's virtually no antagonist activity on dopamine with trazodone.

 

[AlphaMethylPhenyl]

This is stingy but something with 5-HT2a antagonism and no dopamine antagonism could still be labeled anti-psychotic. Also Trazodones work with adrenergic receptors would probably indirectly decrease dopamine and associated amines.

 

[MeDieViL]

5-HT2a agonists include every psychedelic drug that isn't dissociative/deliriant. But Trazodone is primarily a 5-HT2a antagonist without being an antipsychotic, there's virtually no antagonist activity on dopamine with trazodone.

Psychedelics induce secondary intracellular pathways and dont activate the receptor the same as sero, only lisuride does.

5-HT1A receptor (Kd = 78 nM)
5-HT2A receptor (Ki = 13 nM)
5-HT2B receptor (Ki = 74 nM)[24]
5-HT2C receptor (Ki = 192 nM)
α1-adrenergic receptor (Kd = 39 nM)
α2-adrenergic receptor (Kd = 405 nM)
H1 receptor (Kd = 725 nM)
It is an inhibitor of the following transporters as well:[25]
SERT (Kd = 160 nM)

You cant say its mostly a 5HT2A antagonist, its pharmacology is extremely dirty and for example:
"5-HT2A and 5-HT2C receptor antagonists have opposing effects
on a measure of impulsivity: interactions with global 5-HT
depletion"

5-HT2A and alpha1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants.
Auclair A, Drouin C, Cotecchia S, Glowinski J, Tassin JP.
Source
Inserm U.114, Collège de France, 11, Place Marcelin Berthelot, 75231 Paris Cedex 05, France.
Abstract
Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of dopamine (DA) in the ventral striatum. However, recent experiments indicated an implication of alpha1b-adrenergic receptors in behavioural responses to psychostimulants and opiates. We show now that DA release induced in the ventral striatum by morphine (20 mg/kg) is completely blocked by prazosin (1 mg/kg), an alpha1-adrenergic antagonist. However, morphine-induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the alpha1b-adrenergic receptor (alpha1b-AR KO) and in wild-type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine-evoked DA release was completely blocked in alpha1b-AR KO mice by SR46349B (1 mg/kg), a 5-HT2A antagonist. SR46349B also completely blocked, in alpha1b-AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and D-amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5-HT2A and alpha1b-adrenergic receptors in WT mice entirely blocked acute locomotor responses but also the development of behavioural sensitization to morphine, D-amphetamine or cocaine (10 mg/kg). We observed, nevertheless, that inhibitory effects of each antagonist on locomotor responses to morphine or D-amphetamine were more than additive (160%) in naïve WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5-HT2A receptors for the genetic deletion of alpha1b-adrenergic receptors, we postulate the existence of a functional link between these receptors, which vanishes during the development of behavioural sensitization.

All its actions togheter wont give you any idea what just 5HT2A blockade does.

Because a higher percentage of dopamine receptor activation is the "good" receptors and not D2.

This is bullcrap, D2 plays a role in motivation and social behavor, just excessive D2 activation is bad.

Also 5HT2A and 5HT2C agonism is good for atypical depression, them downregulating just causes balance to be shifted so melancholic depressive can benefit too

I´m not sure but I think it is because the abilify binds to the 5HT-2A receptor, which leaves more serotonin to bind to the 5HT-1A receptor. 5HT-1A activation is theorized to be the main mechanism of SSRIs antidepressant activity. 5HT-2A agonism is also why SSRI's cause sexual dysfunction, so this antipsychotic might actually help you get your dick hard!

Of course, mirtazapine will also work, less risk imo.

in 5HT7 knockout rodents abilify is actually pro depressive.

That makes the most sense, and how psychedelics are infamous for causing panic attacks too. 5-HT2c activation inhibits the release of DA and NE, so antagonism lets more DA and NE be released.

Anyway, two questions.

1. If 5-HT1a agonism is arguably the main antidepressant mechanism of SSRIs, then why don't selective 5-HT1a agonists do anything for depression? It may explain how they do something for anxiety, but the one mostly selective 1a agonist we have, buspirone, seems to do fuck all for most people while helping anxiety in the rest.

2. Activation of which serotonin receptor(s) are responsible for the empathogenic effects of MDMA and the like, and how does that activation suddenly make you fall in love with the world and want to be close with people?

Buspirone with a intrinsic activity of 30% will either at low doses raise serotonin or act as a antagonist in high doses replacingsero on the receptor wich activates it for 100%

Also psychedelics dont mimic psychosis, their trip is entirely differened from psychosis, antagonism just augments D2 antagonism .
Also psychedelics dont cause sexual dysfunction as 5HT1A opposes the effects of 5HT2C and 5HT2A, also take in mind they shift phasic sero to tonic (mdai wont cause it if im correct).

Also 5HT2A antagonism does not cause increased da in the pfc, ill back this up in a later post.