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

[AlphaMethylPhenyl]

Surprising that heterodominers have just broken through in this thread. I guess a good example would be A2A/D2, so applying to caffeine.

Also, I think substances become more rewarding if they better facilitate the user's completion of worldly goals. I think stimulants in general are most applicable here. For an artist, it may be something with more hallucinogenic properties. For someone who has to socialize a lot or has a hectic work day, classical depressants.

Something sekio said on the last page about modafinil. I think that it would be a lot more addictive if it entered the brain faster, which is obvious, but I think this gets overlooked. I mean, this is largely what mediates the differential effects of morphine and diamorphine. Yet the latter is much more formidable. So i think we're mostly talking about solubility in lipid in this respect. I remember reading that people have a hard time distinguishing between intravenous cocaine and intravenous methylphenidate.

I know that naloxone can nullify the rewarding effects of many recreational drugs. It's this sort of thing that makes me wonder whether or not we should stop talking about D2 activation and start talking about mu-opiate activation.

Also, I don't think it was explicitly stated that both the region of the brain being activated and not just raising the levels of various NT's but altering the ratio of NT's bears largely on how a substance will produce an effect. Perhaps these factors partly explain how cocaine, with it's ability to raise dopamine levels in the limbic system by ~300%, is oftentimes experienced as more pleasurable than amphetamine, which (as I remember) can do the same but by ~1,000%. Of course serotonergic action and sigma activation also comes into play.

 

[rabidrick]

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

That is kind of the point of a discussion; I wasn't clarifying that just for you.

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?

No, adrenaline is produced in the adrenal medulla which is pretty far away from the brain, itself :V

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.

I hope you don't mean directly connected :V

Also, I'm not clear on what you mean by "most of the psychedelics have been narrowed down to a 5-HT2A/mGlu heterodimer" -- a heterodimer of what two molocules makes what?

5-HT2A is in most of the parts of the brain with high sertonergic activity, but glutamate is the most abundant neurotransmitter and is found pretty much everywhere.

Also, a drug is said to be selective if it targets a certain receptor type. Most things have a cascading effect when it comes to neuroscience.

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's correct.

 

[Cotcha Yankinov]

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.

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.

Cortisol's effects on energy are immediately noticed following elevated blood glucose. Someone with hypoglycemia will surely tell us that sugar levels are important subjectively to one's energy and feeling of well being. There is also a connection between cortisol and 5-HT2C. Stress hormones are important in mediating the subjective effects of drugs though, regular hormones like Oxytocin aside concerning MDMA. "Recent research has linked the activation of the CRH1 receptor with the euphoric feelings that accompany alcohol consumption. A CRH1 receptor antagonist developed by Pfizer, CP-154,526 is under investigation for the potential treatment of alcoholism.^[7][8]"

I shall leave another link to this study concerning amphetamine and 5-HT2's, and of course 5-HT2C's are classically linked with weight gain as well as now stress hormones "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."

Just trying to stress the importance of serotonin as a neuromodulator here. Like I said dopamine and serotonin release in MDMA is not without 5-HT2B, and dopamine increases from amphetamine involve 5-HT2 as well.

 

[rabidrick]

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?

It is likely that would cause an increase in NET expression in the synapses.

I don't know exactly what would happen though, or if it is even possible to get to that point and not die.

Also, I found out what you were talking about regarding 5-HT2A and glutamate heterodimers. I'd have to read up on that as the studies are quite new.

I still have a lot I want to add but have to go do some things first.

I am getting confused though regarding the use of "adrenaline" and the context of the cited journal articles.

For example, I don't understand what people are trying to determine from 5-HT2b which I've seen quite frequently.

Is this just an example of one receptor type influencing another? This is very common and all of these systems are connected.

Dopamine and serotonin also share the same metabolic path, as well.

 

[Cotcha Yankinov]

No, adrenaline is produced in the adrenal medulla which is pretty far away from the brain, itself :V

I hope you don't mean directly connected :V

Also, I'm not clear on what you mean by "most of the psychedelics have been narrowed down to a 5-HT2A/mGlu heterodimer" -- a heterodimer of what two molocules makes what?

5-HT2A is in most of the parts of the brain with high sertonergic activity, but glutamate is the most abundant neurotransmitter and is found pretty much everywhere

I meant noradrenaline I was wondering if noradrenaline occupying the NET could increase the concentration of dopamine by acting as a DRI and thus noradrenaline could lead to increased dopamine without having to resort to general excitatory connections connecting noradrenaline to dopamine.

What I mean about the 5-HT2A is that psychedelics actions are through a 5-HT2A/glutamate heterodimer, and what I am pointing out in this aside from 5-HT2 being incredibly important across the board (even concerning amphetamine and of course MDMA) is that a lot of drugs actions are related to heterodimers. Thus agonists or even reuptake inhibitors effects are not as clean cut as we might think they, save for models utilizing receptor knock outs and selective antagonists. If people understood this they might not spend as much time debating dopamine vs. serotonin vs. noradrenaline highs if they were more conscious that they all connected, and it could matter more about brain region.

BESIDES, we all know euphoria is from those silly opoid receptors

 

[Cotcha Yankinov]

Presynaptic 5-HT2B autoreceptors seem to be necessary for the function of SERT, with drugs that reverse their transporter and dump NT's into the synapse the disabling of the transporter through 5-HT2B knock-out has the same effect as an SSRI regarding MDMA it seems. Models with a 5-HT2B antagonist or knock out mice show they don't get any serotonin OR dopamine release from MDMA, hinting that the dopamine release is primarily mediated through 5-HT, ultimately probably through 5-HT2A. There is the study connecting amphetamines and 5-HT2 as well, that was an older one and that newer MDMA/5-HT2B study said that is something they are working on currently (5-HT2B involvement in amphetamines). Makes me wonder about METH and serotonin, how much dopamine release from meth is through serotonin?

 

[Rio Fantastic]

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.



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.



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.



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.

You seem to know your stuff! How do you know so much about drugs? Where did you learn this? Do you have a degree in a related subject? Have you studied chemistry or biochemistry or anything past high school level? Did you teach yourself?

 

[Rio Fantastic]

I meant noradrenaline I was wondering if noradrenaline occupying the NET could increase the concentration of dopamine by acting as a DRI and thus noradrenaline could lead to increased dopamine without having to resort to general excitatory connections connecting noradrenaline to dopamine.

What I mean about the 5-HT2A is that psychedelics actions are through a 5-HT2A/glutamate heterodimer, and what I am pointing out in this aside from 5-HT2 being incredibly important across the board (even concerning amphetamine and of course MDMA) is that a lot of drugs actions are related to heterodimers. Thus agonists or even reuptake inhibitors effects are not as clean cut as we might think they, save for models utilizing receptor knock outs and selective antagonists. If people understood this they might not spend as much time debating dopamine vs. serotonin vs. noradrenaline highs if they were more conscious that they all connected, and it could matter more about brain region.

BESIDES, we all know euphoria is from those silly opoid receptors

I haven't read most of your post as I'm pressed for time at the moment, I just have two points to raise.

1. You meant noradrenaline? How can I possibly take you seriously now? How can I accept the rest of what you're saying? This is like me making a long, informative post debating the merits of steel vs nickel alloy pickups on guitars or reliability of fenders vs gibson guitars and mixing up a guitar with a double bass. Or its like me engaging in an intellectual discussion on different theories of particle physics and how Hawking radiation can be used to provide support for string theory, and then saying the Earth is flat.

 

[Cotcha Yankinov]

Oh golly, it was a slip of the fingers damnit, I was talking about noradrenaline just forgot to type the Nor Also you only raised one point, I'm just dying to know what the other point was

 

[Rio Fantastic]

Oh golly, it was a slip of the fingers damnit, I was talking about noradrenaline just forgot to type the Nor Also you only raised one point, I'm just dying to know what the other point was

Can't tell if you're being sarcastic or not, but I wanted to raise it anyway so. I see a lot these days that the theory that pleasure & euphoria in our regular daily lives and drug-induced outside of opiates is down to endorphins, but I don't understand *how*. I've taken opiates extensively, from codeine all the way up to heroin. Any experienced opiate junkie knows the opiate high inside and out, obviously. Life as a heroin addict was often a balancing act - how can I make my supply stretch till I next get money, when can I indulge, when do I need to be conserative to avoid getting sick in a couple of days etc. Because of this, after a tester shot of every batch, I knew exactly how much I'd need to get rid of all my sickness (btw this was the mnimum amount id use, i never was one of these who would really really stretch out their supply by using *just* enough to take away all the symptoms, at minimum id use enough to get comfortable), I knew exactly how much I'd need to get slightly high - just enough for a mood lift, for that little opiate cushion that would allow me to drink loads of coffee and get really motivated and focused, and obviously I knew how much to take to gouch my face off and be in bliss.

What I'm getting at here, is no matter what amount I used - whether it was a smallish dose to just lift my mood, a large dose to get really really high, whether it was oxycodone or tramadol/codeine back in the day - all of it would FEEL like an opiate. Whenever I took them I always felt like I was on an opiate, there was no level of use that would just make me happy and raise my mood without feeling some of those good opiate feelings. Since it's the u opiod receptor indicated in all the pleasure of opiates, I can't see how endorphins can be indicated in general happiness & euphoria outside of opiates. Being high on amphetamine for example, is perhaps one of the furthest psychological states from being high on opiates that there is. Cocaine and amphetamine feel different, but you can definitely feel that they're similar drugs - the euphoric, confident, grandiose feeling they give me is nearly identical, the difference being in the extraneous effects, like the levels of energy and how my mind is racing, but the euphoria itself felt extremely similar to me, the difference only being in degree. Both are worlds apart from the hazy, relaxed, extremely contented detached euphoria of opiates. There seems to be zero overlap in the highs, so how can endorphins be responsible for the euphoria of any drug other than opiates? It's late and I've smoked a lot of heroin tonight so I don't know if this makes complete sense, but I hope you see what I'm getting at.

 

[neurotic]

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.

Shit you're probably right... I don't know nothing about neuroanatomy

 

[rabidrick]

I meant noradrenaline I was wondering if noradrenaline occupying the NET could increase the concentration of dopamine by acting as a DRI and thus noradrenaline could lead to increased dopamine without having to resort to general excitatory connections connecting noradrenaline to dopamine.

Yeah, if more transporter isn't expressed as a result that would make sense in the prefrontal cortex.

I have no idea the concentrations needed though, and if that is even feasible.

What I mean about the 5-HT2A is that psychedelics actions are through a 5-HT2A/glutamate heterodimer, and what I am pointing out in this aside from 5-HT2 being incredibly important across the board (even concerning amphetamine and of course MDMA) is that a lot of drugs actions are related to heterodimers.

I read about classic psychedelics but what do you mean by "a lot of drugs?" Is it more than just these?

I also read a journal article from 2013 regarding G-coupled heterodimers and drug discovery so it seemed relatively new in that respect.

Presynaptic 5-HT2B autoreceptors seem to be necessary for the function of SERT, with drugs that reverse their transporter and dump NT's into the synapse the disabling of the transporter through 5-HT2B knock-out has the same effect as an SSRI regarding MDMA it seems.

I believe the reversal of the transporter function has to do with ionic gradient changes, mainly potassium. So the drug can indirectly lead to this.

Models with a 5-HT2B antagonist or knock out mice show they don't get any serotonin OR dopamine release from MDMA, hinting that the dopamine release is primarily mediated through 5-HT, ultimately probably through 5-HT2A. There is the study connecting amphetamines and 5-HT2 as well, that was an older one and that newer MDMA/5-HT2B study said that is something they are working on currently (5-HT2B involvement in amphetamines). Makes me wonder about METH and serotonin, how much dopamine release from meth is through serotonin?

It wouldn't surprise me if many studies correlate 5-HT2 receptor types with aphetamine(s) since it is so prevalent.

Again, these receptors have a regulating function in terms of serotonin.

It is not what *causes* DA release; that is a more direct mechanism of action.

Remember that MDMA is an amphetamine derivative.

The mediation of DA release could also be a result of serotonin upregulation, for example.

You seem to know your stuff! How do you know so much about drugs? Where did you learn this? Do you have a degree in a related subject? Have you studied chemistry or biochemistry or anything past high school level? Did you teach yourself?

Drug nerd since high school, science nerd since... I can remember.

I don't have a degree but I have worked in both biochem and chemistry... Well, the "chemistry" part being work I can't add to a resume.

And yeah, I just read a lot. I'm actually a software developer by trade.

Both are worlds apart from the hazy, relaxed, extremely contented detached euphoria of opiates. There seems to be zero overlap in the highs, so how can endorphins be responsible for the euphoria of any drug other than opiates? It's late and I've smoked a lot of heroin tonight so I don't know if this makes complete sense, but I hope you see what I'm getting at.

The drug acts as an endorphin as it targets some of the same receptors.

The drugs will be very different though, since they target a different variety of receptor types and hence have a different cascade of effects.

 

[PotatoMan]

i think i just figured it out, OP.

when DA is released it regulates the 'expectation of reward' meaning that a lot of DA will make a user expect a lot of reward. what is that reward? OPIOIDS! the natural hormone.

so this is my theory on how DA contributes to euphoria:-- more DA means more reward is expected so more reward is released. so more opioids flood the brain so we begin to feel GOOD.

i don't think this is related to the last few posts but my questions on how dopamine contributes to euphoria is now answered.

so with a re-uptake inhibitor is leaves a lot of dopamine in the synapses so the brain is expecting a lot of reward.

for a releasing agent, the more dopamine released the more reward is expected. so the more DA in your brain the more reward you are expecting.

this could all be crap but what do ya think?

in terms of AMP being more euphoric i guess that's because it releases more monoamines whereas re-uptake inhibitors just trap more.

im getting more confused as i type because this takes me back to the original question which was if we had more DA in our brain before administering a DA re-uptake inhibitor, will we experience more reward than if we didn't?

probably so.. idk this is just a thought