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Question about releasing agents and reuptake inhibitors.

J

JackiesBabyy

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May 16, 2011
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Okay, so I've been told that SSRIs block most of MDMA's serotonin releasing effects because the SERT is already occupied, thus blocking the serotonin.

But, for example, 4-FA is both a DARI and a dopamine releasing agent. How do these not cancel each other out like combining an SSRI with MDMA?

In addition, I've heard people say bupropion (DARI) potentiates the effects of adderall (DA releaser).
 
Dopamine releasing agents are also considered to be reuptake inhibitors. Generally how it work is low doses block the transporter and higher doses cause it to reverse & spew monoamines out.

The reason MDMA is blocked by SSRIs is because the SSRI's bind very tightly to the serotonin transporter and MDMA cannot bind to perform its magic. (note: 2 different drugs at work) This same process will happen with dopamine/norepinephrine to a lesser extent.

A similar analogy would be it's useless to take up IV heroin with buprenorphine in your system. The heroin won't end up binding to the receptors because it's being blocked by a compound with higher affinity.

It's hard to reuptake monoamines when the cell is busy emptying them into the synapse.

Buproprion mixed with amphetamines will potentiate it to some extent but it will also raise seizure risk.

The amphetamines are considered to be dose-dependent releasing/reuptake inhibitors and they bind fiarly noncompetitively, so this effect is never seen with amphetamines alone. Some people find mixing e.g. ritalin and amphetamine will decrease the effects of both, though.


See also this thread
 
I believe i once read, at low doses amphetamine acts primary as a reuptake inhibitor. Is that true?
 
It is my understanding that releasing agents are also reuptake inhibitors (esp. at lower doses, below the threshold needed to cause release) but not all reuptake inhibitors are releasers.
 
Select both the option on animations for 'with cocaine' & 'without cocaine' & 'with amphetamine' & 'without amphetamine' to see it drawn out for you.

Releaser

Re-uptake inhibitor

DRIs are not DRAs at all, but DRAs 'traffick jam' the re-uptake pumps and in large quantities have DRI type action also, but not the other way around.
 
Don't releasers enhance DA release via VMAT2?

reuptake inhibitors do so by blocking DAT. They're two different proteins being effected.
 
Hammilton said:
Don't releasers enhance DA release via VMAT2?

reuptake inhibitors do so by blocking DAT. They're two different proteins being effected.
Click to expand...

They both interact with the plasma membrane transporters (DAT/NET/SERT) but in different ways. Releasing agents work in a sort of 4 step process (although some of this action is more concurrent than sequential):

1. Releasing agents acts as a substrates for the plasma membrane tranporter (drug taken from synapse->cytosol)
2. Then as substrates for VMAT2 (drug taken from cytosol->vesicles)
3. Then triggers release from vesicles (neurotrasmitter from vesicle -> cytosol)
4. Then causes the plasma membrane transporter to work in reverse (neurtransmitter from cytosol->synapse).

So if you look at the first step in that process it's pretty clear why an SSRI would block the effects of MDMA. If the SSRI is blocking reuptake MDMA won't be taken up into the cytosol, and the next three steps can't occur.
 
hammilton said:
Don't releasers enhance DA release via VMAT2?

reuptake inhibitors do so by blocking DAT. They're two different proteins being effected.
Click to expand...

Known recreational dopamine releasers are active at VMAT2 but also at dopamine and norepinephrine transporters. I'm not sure whether this is true of selective serotonin releasers, but I would wager that it is not, given that VMAT2 isn't selective in what it transports.

ebola
 
Well, keep in mind that a lot of the way that amphetamine actually works as an NDRI is by competitive inhibition; that is, the transporter is too busy sucking up amphetamine to suck up too much dopamine/norepinephrine. That doesn't mean it's necessarily sitting in the transporter like a plug in a drain.

A reuptake inhibitor certainly can block a releaser from acting on a transporter, but usually this effect is not large enough that it cancels out the additive monoamine concentration raising effects of the two drugs. So, if you take 20 mg of amphetamine, it may do more to take 20 more mg of amphetamine than take 30 mg of methylphenidate; however, the 30 mg MPH on top of 20 mg amph will still cause increased stimulation.

As far as bupropion goes... well, it's a weird drug. It doesn't seem to behave like normal NDRIs, so there's probably something more going on. That could be its anticholinergic effect, which might potentiate amph.
 
Well first off, from my own experience I can at least say that bupropion feels different from other NDRIs... more subtle. Also, I don't think there are any other NDRIs which actually maintain any antidepressant efficacy without rapidly scaling up in dose, or take over a week to take effect. Then there's also its strange properties of lowering the seizure threshold and acting as a local anesthetic...
 
atrollappears said:
A reuptake inhibitor certainly can block a releaser from acting on a transporter, but usually this effect is not large enough that it cancels out the additive monoamine concentration raising effects of the two drugs. So, if you take 20 mg of amphetamine, it may do more to take 20 more mg of amphetamine than take 30 mg of methylphenidate; however, the 30 mg MPH on top of 20 mg amph will still cause increased stimulation.
Click to expand...
why is it the case then that SRIs do cancel the action of SRAs?

another question which troubles my mind since a long time: how comes it that SRIs and NRIs act as antidepressants and, as such, have only subtle effects, while DRIs are powerful stimulants (at least some of them)?
 
ungelesene_bettlek said:
why is it the case then that SRIs do cancel the action of SRAs?

another question which troubles my mind since a long time: how comes it that SRIs and NRIs act as antidepressants and, as such, have only subtle effects, while DRIs are powerful stimulants (at least some of them)?
Click to expand...

SRIs cancel out SRAs because SRIs do not acutely raise synaptic serotonin levels to any significant extent. This is because 5-HT1A autoreceptors decrease serotonin release with any rise in concentration. That these receptors must be desensitized/downregulated before SRIs can increase synaptic serotonin levels is one of the reasons for the delayed onset of action of SSRIs.

The thing about serotonergic pathways is that they're mostly just regulatory. They don't really signal any specific behavior; rather, they convey vague signals about environmental conditions. Thus they do not generally cause any huge alteration in behavior when activated alone. I don't know much about NRIs, but I'm willing to bet that if you took enough of one you would certainly experience strong effects, though they wouldn't be good ones (and that goes for SRIs too at extreme doses). Now, selective DRIs, I'm told, are actually pretty much just compulsion-inducers. The interesting thing is that for one to produce stimulant effects like those of amphetamines/MPH/cocaine, one must elevate both NE and DA.
 
atrollappears said:
SRIs cancel out SRAs because SRIs do not acutely raise synaptic serotonin levels to any significant extent. This is because 5-HT1A autoreceptors decrease serotonin release with any rise in concentration. That these receptors must be desensitized/downregulated before SRIs can increase synaptic serotonin levels is one of the reasons for the delayed onset of action of SSRIs.

The thing about serotonergic pathways is that they're mostly just regulatory. They don't really signal any specific behavior; rather, they convey vague signals about environmental conditions. Thus they do not generally cause any huge alteration in behavior when activated alone. I don't know much about NRIs, but I'm willing to bet that if you took enough of one you would certainly experience strong effects, though they wouldn't be good ones (and that goes for SRIs too at extreme doses). Now, selective DRIs, I'm told, are actually pretty much just compulsion-inducers. The interesting thing is that for one to produce stimulant effects like those of amphetamines/MPH/cocaine, one must elevate both NE and DA.
Click to expand...
thank you a lot for your extensive answer! it made a lot of thing clearer to me.

but one question did newly arise: how do the things you said about serotonergic pathways fit with the strong effects of 5HT2A agonists?
 
I have another related question. Why are norepinephrine releasing agents like ephedrine stimulating yet NRIs(Like strattera, not NDRIs like ritalin and bupropion) are sedating for most people? Main side effect of strattera is somnolence.
 
Most of what people consider "norepinephrine releasing agents" have activity at alpha/beta adrenergic receptors, DAT, and even at SERT. They're dirty drugs. Ephedrine in particular is stimulating because of its alpha-adrenoreceptor (ant)agonism.
 
sekio said:
Most of what people consider "norepinephrine releasing agents" have activity at alpha/beta adrenergic receptors, DAT, and even at SERT. They're dirty drugs. Ephedrine in particular is stimulating because of its alpha-adrenoreceptor (ant)agonism.
Click to expand...

It also has mild dopamine release too seeing as it provides mild euphoria/a mood lift and some focus to a non-tolerant person. (And wikipedia says so :p)

Plus doesn't lots of NE get released during the fight-or-flight response which = stimulated? What do you think a pure NRA would feel like? As in, did nothing by itself except release NE. (or at least one that's highly selective for NE with negligible dopamine/5-ht release)
 
Sometimes dopamine/norepinephrine/epinephrine are injected direct IV for various trauma/cardiac things. I cannot imagine they are very pleasant.

Yohimbine is an alkaloid that acts at autoreceptors to release norepinephrine/adrenaline - it's not considered to be very fun at all

Ask the moron kids who abuse Epi-Pens (or people with past occurences of anaphylaxis) how fun it is. I think epinephrine is not controlled for a reason...
 
sekio said:
Sometimes dopamine/norepinephrine/epinephrine are injected direct IV for various trauma/cardiac things. I cannot imagine they are very pleasant.

Yohimbine is an alkaloid that acts at autoreceptors to release norepinephrine/adrenaline - it's not considered to be very fun at all

Ask the moron kids who abuse Epi-Pens (or people with past occurences of anaphylaxis) how fun it is. I think epinephrine is not controlled for a reason...
Click to expand...

Yohimbe is fun mixed with weed and nothing else. but alone it just makes me feel like my blood pressure skyrocketed. And I don't think dopamine injections are fun because dopamine doesn't cross the BBB.
 
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