Difference between a reuptake inhibitor and a "releasing agent" in terms of dopamine

[aced126]

If we had reward systems that never produced tolerance, the result would be people would sit in one place jacking off until they died.

This made me lol

 

[neurotic]

trying to explain complex phenomenons such as feelings in molecular terms is very tricky; there is much, much more going on. lots of people find stimulants unpleasant, you can still have a bad time on MDMA while your brain is flooded with monoamines or get seriously pissed off while high on opiates. even tolerance, which seemed (to me) to be mainly neurochemical, is very 'sensitive' to other stuff such as environmental cues even.

 

[Rio Fantastic]

It's a prodrug for cathinone, not methcathinone, but I don't see how that's relevant. The onset of effects is too rapid for it to be a prodrug. Even cathinone itself is mostly a norepinephrine releaser.

Regfarding the fight or flight response, again, norepinephrine is not the only neurotransmitter involved. NE is elevated in all states of arousal and looking at NE levels in the brain alone is missing the forest for the trees.



That's a gross oversimplification. Beta blockers block the effects of norepinephrine and adrenaline at one specific type of adrenergic receptor. They are not global "norepinephrine blockers". Alpha-2 agonists are probably the closest thing to "anti-adrenergic" (NE/Adrenaline) blockers - drugs like clonidine - these work by confusing your brain into thinking NE/adrenaline levels are higher than they actually are, resulting in a global decrease in NE/adrenaline release. Curiously enough, this has a powerful effect at decreasing ability to concentrate/awareness, so much so that clonidine is used as a sedative in some cases.

Here's a reference for you: MDMA's effects in humans are greatly reduced if you block norepinephrine release at NET. It is also worth your time to look at the affinity to the various transporters for a drug like, say, amphetamine or methylone.

Also, more trivia: the norepinephrine transporter will actually transport dopamine, with lower affinity than NE. And the dopamine transporter will transport NE in the same fashion. So presumably even "selective" NET blockers will provide some level of DA elevation.

My opinion on the whole tolerance issue, by the way, is that the dopaminergic/reward systems need to desensitize themselves to recurrent stimuli. Tolerance to rewarding stimuli is part of what drives the human experience, particularly the feeling of boredom and desire for novel experiences. If we had reward systems that never produced tolerance, the result would be people would sit in one place jacking off until they died.

The dopamine system in particular is how our brain adjusts our expectations of reward.[ref] As I understand it, DA release in the nucleus accumbens (reward centres) is highest in the case of an action which, while not expected to produce a reward with high likelihood, does occur. Think hitting a jackpot at a slot machine, or being pleasantly suprised someone left you a large cash gift, or finding out your wife is pregnant after trying to have a baby for months. In the case where reward is fully expected, DA release is nonexistent. For instance, a salaried worker who has been at his job for ten years doesn't really get a rush of pleasure having his bimonthly paycheck deposited, because it happens every 15 days without fail. Likewise, a slot machine where you won every time would not be as intrinsically "hooking" as one that had a 50% probability of a win.

Thank you for correcting me about how beta-blockers work, after looking into it briefly I can see my thoughts on how they work were so, so oversimplified as to just be essentially completely wrong. Thank you for elaborating - this is how we learn, no? I concede I was wrong and that it is indeed a pro-drug for cathinone and not methcathinone. However, I would like to add that ethcathinone still has a weak effect on dopamine transmission and is turned into cathinone in the body relatively quickly, and so still could account for some of the reinforcing properties of the drug. I didn't claim it was only a prodrug, I specifically said I realize it's psychoactive in its own right, just that it's not great evidence of norepinephrine being the neurotransmitter responsible for pleasure in the absence of dopamine release due to it ALSO being a prodrug for cathinone.

Fair enough that the fight or flight response is irrelevant for some reason, despite being *primarily* mediated by norepinephrine, I guess if you say that it's irrelevant then it's irrelevant.

Also, okay, we can use clonidine as the example if you like. There are also plenty of anecdotal reports of people using clonidine to counter stimulant anxiety. Quite a few reports of people using it to successfully calm down whilst maintaining a stimulant-type high. I have yet to find the report that you would expect - where clonidine is used concurrently to stimulants, and blocks the euphoria/high/pleasurable response, as it is your argument that noradrenaline is the neurotransmitter that's primarily involved in the perception of pleasure rather than dopamine.

Your commentary on tolerance and the dopamine system makes sense, and I fully agree with it. You appear to be backpedalling a little now though - until now you have maintained the position that dopamine is all about the anticipation of pleasure and wasn't actually involved in the perception of pleasure itself - this is what we have been debating the past few posts. Have you now decided to change your mind?

If I could get back to ethcathinone for a moment - you used it as your example of a stimulant that proved your point about norepinephrine alone being reinforcing and pleasurable alone in the absence of DAT. However, as I've mentioned as well as being psychoactive in its own right it is also a prodrug for a substance that does act on dopamine, and also you mention in this very post that the norepinephrine transporter can move dopamine and vice versa? Now, doesn't this mean that trying to look at ANY stimulant as working on "just" dopamine or "just" norepinephrine is totally useless since apparently they can both be moved by the other corresponding transporter!? And couldn't this also explain why an agent that apparently only releases norepinephrine could be reinforcing - as the norepinephrine transporter can transport dopamine also? Don't these two facts together make your example of a norepinephrine-only stimulant a little worthless, since not only is that stimulant a pro-drug for something that works on dopamine, but you have just said the norepinephrine transporter works on dopamine also?

Also, I did take a look at that study of yours. Without seeing a little more than the abstract it will be difficult for me to draw any firm conclusions from it, though at first glance I concede it appears to support your proposition. However, I know that the dopamine release in MDMA is a downstream one - perhaps the reaction that leads to the dopamine release and the eventual high is dependent on the release of norepinephrine at some stage? Or perhaps the dose of MDMA was quite low? Like I said, it's really hard to draw any conclusions without being able to read the full study.

I did stumble upon some other binding affinities, however. I'd appreciate it if you told me where one of them in particular fit into your framework - on this Wikipedia page , there is a table detailing the selectivites of several drugs - am I right in thinking that this is the same as the binding affinities? Anyway, if you direct your attention to "pseudoephedrine", you'll notice it has quite a high affinity for norepinephrine - indeed, it is my understanding it only works on norepinephrine and not dopamine or serotonin. Now, why does norepinephrine have to be turned into meth/amphetamine before it becomes a rewarding, euphoric stimulant? If it works on norepinephrine already why is pseudoephedrine not already a euphoric and enjoyable substance?

Also, while we're having a discussion, I'd appreciate it if you either didn't reply to my entire post (and conceded defeat, haha) or replied to all of it, it's pretty irritating how you'll pick out one or two points to respond to, add some filler by talking around the topic, and then ignore the rest of the post that you don't feel like dealing with.

 

[sekio]

Fair enough that the fight or flight response is irrelevant for some reason, despite being *primarily* mediated by norepinephrine, I guess if you say that it's irrelevant then it's irrelevant.

When did I say that? I don't contest the fact that norepinephrine release plays a part in the fight-or-flight response, but at the same time, I maintain the position that the elevation of a single neurotransmitter's concentrations in a certain area of the brain can't tell you with certainty about the mental state of that individual.

until now you have maintained the position that dopamine is all about the anticipation of pleasure and wasn't actually involved in the perception of pleasure itself

Let me elaborate a little. This really hinges on the definition of "pleasure". Do we feel pleasurable when we get an unexpected reward? Yes. But obviously, we don't only feel rewarded when we have unexpected experiences. There is a lot involved in the perception of pleasure, more than a single neurotransmitter. that's the point I mean to get across.

If I could get back to ethcathinone for a moment - you used it as your example of a stimulant that proved your point about norepinephrine alone being reinforcing and pleasurable alone in the absence of DAT. However, as I've mentioned as well as being psychoactive in its own right it is also a prodrug for a substance that does act on dopamine, and also you mention in this very post that the norepinephrine transporter can move dopamine and vice versa? Now, doesn't this mean that trying to look at ANY stimulant as working on "just" dopamine or "just" norepinephrine is totally useless since apparently they can both be moved by the other corresponding transporter!?

You know what? I suspect that some of its activity in man is due ot its metabolism to cathinone, but I cannot be sure.

And you are totally correct about there being no one stimulant that "only releases DA" or "only releases NE". If you think about it, nothing in the brain occurs in vacuo...

It is also good to remember that even though the NE transporter can move dopamine around (and vice versa), the transporters are located in different areas (on different cells) and they do have a preference for their "own type" of monoamines.

We haven't even got to arguing about the vesicual monoamine transporter, either (VMAT)

I know that the dopamine release in MDMA is a downstream one

Where did you hear that? MDMA is a triple releasing agent, it causes the release of NE, DA, and 5HT. DA release is not exclusively downstream.

there is a table detailing the selectivites of several drugs - am I right in thinking that this is the same as the binding affinities?

That is correct. Ki values are binding affinities.

Anyway, if you direct your attention to "pseudoephedrine", you'll notice it has quite a high affinity for norepinephrine - indeed, it is my understanding it only works on norepinephrine and not dopamine or serotonin. Now, why does pseudoephedrine have to be turned into meth/amphetamine before it becomes a rewarding, euphoric stimulant? If it works on norepinephrine already why is pseudoephedrine not already a euphoric and enjoyable substance?

It was my understanding that the monoamine releasing properties of pseudoephedrine are relatively weak compared to its activity directly stimulating adrenergic receptors (e.g. acting as a substitute for adrenaline/NE). I know that ephedrine is occaionally abused, and I have also heard of pseudoephedrine abuse too, rare as it may be.

Please, keep asking questions. I don't mind answering them, it helps me clarify my own thoughts on this issue too.

 

[Cotcha Yankinov]

Thought I would throw 5-HT2B into this discussion, very interesting serotonin receptor...

from "http://www.jneurosci.org/content/28/11/2933.long" citations removed for clarity -

"When access to SERT is blocked by fluoxetine (an SSRI), the MDMA-evoked DA efflux in the striatum is reduced. Moreover, tetrodotoxin infusion in the striatum reduces the extracellular concentration of DA evoked by MDMA. In other words, MDMA-induced DA release involves stimulation of postsynaptic 5-HT receptors after SERT-dependent 5-HT release. These data are supportive of a stimulatory role of 5-HT in the regulation of dopamine release. Moreover, DAT expression and function are not altered in 5-HT_2B^−/− mice. Thus, inhibition of DA release in NAcc seen in 5-HT_2B^−/− and in RS127445-treated mice after MDMA administration may be attributed to the absence of 5-HT release in VTA and/or NAcc, where postsynaptic 5-HT_2A and 5-HT₃ receptors have stimulatory effect, respectively. Whether non-5-HT-selective releasers such as d-amphetamine may also be affected by 5-HT_2B receptor activity is currently under investigation in our laboratory. Additional studies are also underway to ascertain the direct or indirect role of 5-HT_2B receptor in the action of MDMA on DA release."

from "http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007952" -

"Activation of the mesolimbic dopaminergic system, which consists of projections from the midbrain ventral tegmental area (VTA) to forebrain regions, including the nucleus accumbens (NAcc), is critical for the psychostimulant and reinforcing effects of drugs of abuse [1]. Dopamine (DA) increase in the NAcc plays a critical role in reward and drug dependence and is a common response generated by all drugs of abuse [1]. On the other hand, emerging data support a role of serotonin (5-HT) in the rewarding effects of psychostimulants [2]. Serotonergic neurons from the dorsal raphé nucleus project to the VTA and the NAcc and impact dopaminergic neurotransmission [2], [3]. Thus, regulation of mesolimbic DA activity by 5-HT and its receptors plays an important role in the reinforcing effects of drugs of abuse [4], including the ‘club drug’ MDMA [5]–[8].

MDMA binds to and reverses the dopamine transporter (DAT) and the serotonin transporter (SERT) to produce carrier-mediated efflux of DA and 5-HT, respectively [9]. However, when access to SERT is blocked by selective serotonin reuptake inhibitors (SSRI), MDMA-evoked DA efflux in the NAcc is reduced [10]–[12]. In humans, relevant studies have shown that most of MDMA's effects are also markedly reduced after administration of 5-HT receptor antagonists or SSRIs, suggesting that these effects depend on SERT-mediated enhancement of 5-HT transmission [13]. In other words, MDMA-induced DA release in the NAcc is only partially carrier (DAT) - mediated but also involves a SERT-dependent 5-HT release."

 

[Foreigner]

I don't have the academic know-how to really form my own reply but I just wanted to say this thread is super fascinating. Thanks all

 

[rabidrick]

Hello,

Just a quick question about the difference between the psychopharmacology of drugs like cocaine or Ritalin vs drugs like amphetamine/methamphetamine. It is my (admittedly very basic & limited) understanding that cocaine and methylphenidate work by blocking the dopamine transporter, so not actively releasing dopamine but just inhibiting its reuptake into the synapse, whereas meth/amphetamine work by actively making the transporters reverse direction and release dopamine into the synapse.

Technicality, but a reuptake inhibitor would inhibit its reuptake out of the synapse and into the cytosol. Also, amphetamine is both a reuptake inhibitor and releases catecholamines (the medical definition of an amphetamine being a drug that releases chatecolamines, not to be confused with amphetamine * hcl). Regarding cocaine, it is more specific to norepinephrine but affects all three.

>> does that mean that the effect or high you get off of cocaine/ritalin is somewhat dependent on how much dopamine transmission there was anyway

Yes, for example caffeine, which is a cyclic AMP phosphodiesterase inhibitor (this has to do with a G-protein coupled receptor that ultimately increases the number of open sodium channels, bringing the voltage closer to action potential) basically makes the norepinephrine system "more efficient" and this will have a synergistic effect with cocaine as will NE agonists, etc.

If so, then does that mean that cocaine/ritalin would be significantly more pleasurable if taken when you're already in a relatively "high-dopamine" state, i.e. after sex or a meal or just when you're in a good mood as compared to when you're in a regular mood or a low dopamine-state?

Dopamine levels are not increased after sex, however they are before and during and as with satiating hunger these are mainly in the limbic system. This won't necessarily make it more pleasurable but a reuptake inhibitor will cause people to eat less and get horny again sooner =P

Also, if amphetamine actually facilitates the release whereas coke just stops it being taken back up, why is it that subjectively I, along with many others, can get a more euphoric high from a cocaine peak than from an amphetamine peak (can't speak for meth never tried it)?

Your brain is unique and something won't necessarily affect you in the same way as it will others.

 

[Rio Fantastic]

When did I say that? I don't contest the fact that norepinephrine release plays a part in the fight-or-flight response, but at the same time, I maintain the position that the elevation of a single neurotransmitter's concentrations in a certain area of the brain can't tell you with certainty about the mental state of that individual.



Let me elaborate a little. This really hinges on the definition of "pleasure". Do we feel pleasurable when we get an unexpected reward? Yes. But obviously, we don't only feel rewarded when we have unexpected experiences. There is a lot involved in the perception of pleasure, more than a single neurotransmitter. that's the point I mean to get across.



You know what? I suspect that some of its activity in man is due ot its metabolism to cathinone, but I cannot be sure.

And you are totally correct about there being no one stimulant that "only releases DA" or "only releases NE". If you think about it, nothing in the brain occurs in vacuo...

It is also good to remember that even though the NE transporter can move dopamine around (and vice versa), the transporters are located in different areas (on different cells) and they do have a preference for their "own type" of monoamines.

We haven't even got to arguing about the vesicual monoamine transporter, either (VMAT)



Where did you hear that? MDMA is a triple releasing agent, it causes the release of NE, DA, and 5HT. DA release is not exclusively downstream.



That is correct. Ki values are binding affinities.



It was my understanding that the monoamine releasing properties of pseudoephedrine are relatively weak compared to its activity directly stimulating adrenergic receptors (e.g. acting as a substitute for adrenaline/NE). I know that ephedrine is occaionally abused, and I have also heard of pseudoephedrine abuse too, rare as it may be.

Please, keep asking questions. I don't mind answering them, it helps me clarify my own thoughts on this issue too.

This is pointless, you repeatedly have cherry-picked the parts of my post you find it relatively easy to answer and totally ignored the rest. This is has happened 3 times now, you've even ignored the part where I ask you not to do it, it's rendering the entire debate redundant.

 

[rabidrick]

Regfarding the fight or flight response, again, norepinephrine is not the only neurotransmitter involved. NE is elevated in all states of arousal and looking at NE levels in the brain alone is missing the forest for the trees.

In all fairness, when people are talking about a sympathomimetic (fight or flight) response they are generally referring to the sympathetic adrenergic system. This is mainly due to adrenaline (epinephrine) and noradrenaline (norepinephrine).

Now, doesn't this mean that trying to look at ANY stimulant as working on "just" dopamine or "just" norepinephrine is totally useless since apparently they can both be moved by the other corresponding transporter!?

I think this might be getting monoamine transporters confused with monoamine oxidase.

There are different transporters for the different chatecholamines but monoamine oxidase is fairly non-specific.

 

[neurotic]

the catecholamines do have a degree of affinity for each other's transporter (DA and NET, NE and DAT). given how similar molecules they are, not very surprising.

 

[Rio Fantastic]

In all fairness, when people are talking about a sympathomimetic (fight or flight) response they are generally referring to the sympathetic adrenergic system. This is mainly due to adrenaline (epinephrine) and noradrenaline (norepinephrine).

I think this might be getting monoamine transporters confused with monoamine oxidase.

There are different transporters for the different chatecholamines but monoamine oxidase is fairly non-specific.

Read the post I was quoting.

 

[rabidrick]

the catecholamines do have a degree of affinity for each other's transporter (DA and NET, NE and DAT). given how similar molecules they are, not very surprising.

Yes, in a binding assay they would. They are all monoamines. Generally though, the specific transporter is responsible for its monoamine with the main exception being NET in the prefrontal cortex. That is what I was getting at; they really can't be moved by any transporter since they are only expressed in certain areas in the brain with relevant activity.

Read the post I was quoting.

I did. If you give me some actual context I'd have an idea what you are referring to :V

 

[Rio Fantastic]

Yes, in a binding assay they would. They are all monoamines. Generally though, the specific transporter is responsible for its monoamine with the main exception being NET in the prefrontal cortex. That is what I was getting at; they really can't be moved by any transporter since they are only expressed in certain areas in the brain with relevant activity.

I did. If you give me some actual context I'd have an idea what you are referring to :V

It wasn't my assertion, I just took what seiko said to be true, and was debating on the principle that it's correct. Here's what he said:

Also, more trivia: the norepinephrine transporter will actually transport dopamine, with lower affinity than NE. And the dopamine transporter will transport NE in the same fashion. So presumably even "selective" NET blockers will provide some level of DA elevation.

 

[Cotcha Yankinov]

In all fairness, when people are talking about a sympathomimetic (fight or flight) response they are generally referring to the sympathetic adrenergic system. This is mainly due to adrenaline (epinephrine) and noradrenaline (norepinephrine).

Let us not forget the almighty stress hormones such as cortisol, cortisol is elevated by 800% in MDMA club goers.

It does appear neurotic's linked paper answers a lot of questions. MDMA's release of NT's is not without 5-HT2B so its kind of a unique one, they are investigating 5-HT2B's involvement with amphetamines as well though so who knows. What does make sense to me is that a dopamine re-uptake inhibitor wouldn't make tics and such too much worse because you're (for the most part) firing dopamine circuits that are already activated even more, as opposed to a dopamine agonist that would be activating non previously activated dopamine circuits. If you already have tics a DRI would make the tics worse because you're already using those brain circuits, where as you would need a dopamine agonist to easily give a normal person tics.

The intuition that a DRI would make things that already use dopamine use even more dopamine is likely correct, but euphoria is no simple matter. A lot of it might have to do with specific structures/pathways in the brain and might not be specifically located to a single NT, though a certain NT might be abundant in a pathway associated with "reward" or "anticipation of a reward".

Does L-Dopa cause euphoria? Or does L-dopa just increase stores of dopamine in the brain and would therefore be more functionally similar to a DRI than a dopamine agonist? (In the sense that might it only increase the firing rate of dopamine cells that are already firing if it just increases the stores of dopamine in vesicles).

 

[rabidrick]

It wasn't my assertion, I just took what seiko said to be true, and was debating on the principle that it's correct. Here's what he said:

Norepinephrine transporters are not expressed in neurons that produce dopamine, however it is responsible for clearing of the majority of dopamine in the prefrontal cortex.

However, many drugs themselves targeting these are non-specific, which might explain the lack of specificity.

The DAT is produced in areas of the brain in loci specific to dopaminergic activity.

 

[Rio Fantastic]

Norepinephrine transporters are not expressed in neurons that produce dopamine, however it is responsible for clearing of the majority of dopamine in the prefrontal cortex.

However, many drugs themselves targeting these are non-specific, which might explain the lack of specificity.

The DAT is produced in areas of the brain in loci specific to dopaminergic activity.

Okay, but why are you telling me this? It's not me who made the claim.

 

[Cotcha Yankinov]

Could increased adrenaline (with its high affinity for NET) essentially soak up the NETs in the PFC and thereby leave more dopamine hanging around with not as many NET's to clear it?

Glutamate is very important concerning excitatory highs as well, most of the psychedelics have been narrowed down to a 5-HT2A/mGlu heterodimer, but 5-HT2A and glutamate connect to most everything. On that note there is the connectivity view of the brain, which is essentially that most brain cells connect to most brain cells. Heterodimers are everywhere.

No drug is ultimately selective if the brain cell it is selective for connects to other types of brain cells.

 

[Rio Fantastic]

Could increased adrenaline (with its high affinity for NET) essentially soak up the NETs in the PFC and thereby leave more dopamine hanging around with not as many NET's to clear it?

This goes to show just how little I know. I thought that adrenaline was a hormone and didn't readily cross the blood-brain-barrier and so the level of adrenaline in the body wouldn't have any effect on norepinephrine or dopamine levels in the brain. That aside though, the norepinephrine transporter may be able to take up dopamine as well, but its not as if thats its primary function or that its the main transporter involved in the reuptake of dopamine - obviously, DAT does that, so my first thought would be that it would have little to no effect on overall dopamine levels considering the DAT transporter is the primary vescicle for clearing dopamine from the synapse & the brain wouldn't require the NET for that purpose. Also, if that were true, when it came to stimulants that work on both dopamine & norepinephrine, one would expect to see that the ones that raise dopamine levels the most corelate with the ones that simultaneously block NET, which isn't always the case - there are plenty of stimulants that only have a small effect on dopamine levels but are very efficient at raising norepinephrine levels. However, like I said, my knowlege of neuroscience, chemistry and psychopharmacology is extemely limited - I know next to nothing and reading this subforum regularly drives me to the brink of self-harm with how frustrating it is to be confronted with my own lack of proficiency in a subject I'm so fascinated by.

 

[rabidrick]

Let us not forget the almighty stress hormones such as cortisol, cortisol is elevated by 800% in MDMA club goers.

Cortisol and other such hormones take a great deal of time to "kick in." It is not something that can be used as an analogy to drugs targeting these receptors that work in under an hour. Also, cortisol is called a "stress hormone" because it *is caused by* stress. If anything it triggers changes that help mitigate stress. It also has nothing to do with a fight or flight response aside from sympathetic responses like that triggering the release of cortisol.

It does appear neurotic's linked paper answers a lot of questions. MDMA's release of NT's is not without 5-HT2B so its kind of a unique one, they are investigating 5-HT2B's involvement with amphetamines as well though so who knows.

I read the post but it looked like a bunch of copy pasta from journal articles. Yes, 5HT-2b is targeted in hallucinogenic *substituted* amphetamines (not amphetamine * hcl itself, at least as far as I am aware) which explains the cross-tolerance with acid. What exactly were the questions you were trying to answer? The 5-HT2 receptors are regulatory and mediate serotonin via its transporter and also heart function.

What does make sense to me is that a dopamine re-uptake inhibitor wouldn't make tics and such too much worse because you're (for the most part) firing dopamine circuits that are already activated even more, as opposed to a dopamine agonist that would be activating non previously activated dopamine circuits. If you already have tics a DRI would make the tics worse because you're already using those brain circuits, where as you would need a dopamine agonist to easily give a normal person tics.

The intuition that a DRI would make things that already use dopamine use even more dopamine is likely correct, but euphoria is no simple matter. A lot of it might have to do with specific structures/pathways in the brain and might not be specifically located to a single NT, though a certain NT might be abundant in a pathway associated with "reward" or "anticipation of a reward".

It isn't really intuition; it's been studied extensively. If you go to pubmed and search for methylphenidate and obesity for example. Some drugs can cause euphoria and this has been associated with dopamine. These will generally cascade into a variety of different effects targeting a number of receptors and pathways. Human happiness, on the other hand, certainly not be boiled down to receptor/ligand. That would be a ridiculous assertion since many events connected in many complex ways lead to it.

Does L-Dopa cause euphoria? Or does L-dopa just increase stores of dopamine in the brain and would therefore be more functionally similar to a DRI than a dopamine agonist? (In the sense that might it only increase the firing rate of dopamine cells that are already firing if it just increases the stores of dopamine in vesicles).

L-dopa is used to treat Parkinsons and certain cases of dystonia. It is a precursor of both norepinephrine and dopamine as well as adrenaline. It is mainly metabolized in the peripheral nervous system so in this case it wouldn't do much. Administered with something like carbidopa I would not be surprised if it had the potential for abuse but probably has a limit where L-amino acid decarboxylase is inhibited. It would lead to more DA in vesicles if it leads to more extracellular dopamine.

 

[Cotcha Yankinov]

Sorry I should've been more specific and said "Noradrenaline" and not Adrenaline, but all this involves the HPA axis at least. https://www.ncbi.nlm.nih.gov/pubmed/16386715 - "Dopamine-mediated actions of ephedrine in the rat substantia nigra"
The NET does indeed handle the dopamine clearance in the PFC, my pondering was since the NET has higher affinity for noradrenaline than dopamine wouldn't it make sense that noradrenaline could increase dopamine concentrations by occupying enough NET, therefore acting as a indirect dopamine reuptake inhibitor?

Does that make sense to anyone else that the adrenaline could work as an indirect dopamine reuptake inhibitor in this way?

The weird thing about the adrenaline receptors is that a lot of them are auto receptors. Then again a lot of serotonin receptors are auto receptors, and the 5-HT2B presynaptic auto receptors are necessary for both the dopamine and serotonin release caused by MDMA, though MDMA is a 5-HT2B agonist.

Has anyone heard anything else about 5-HT2B and more classical "adrenergic/dopamine" stimulants? One study said that studies were under way to ascertain to important of 5-HT2B in amphetamines, and that was fairly recently. I only know of this study - "http://www.ncbi.nlm.nih.gov/pubmed/11850146" - 5-HT2A and 5-HT2C/2B receptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and striatum.

I think the important of serotonin as a neuromodulator of dopamine is understated.