aced126
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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
N&PD Moderators: Skorpio | someguyontheinternet
If we had reward systems that never produced tolerance, the result would be people would sit in one place jacking off until they died.
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.
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.
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
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!?
I know that the dopamine release in MDMA is a downstream one
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 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?
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.
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?
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)?
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.
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.
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!?
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.
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.
Read the post I was quoting.
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
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.
Let us not forget the almighty stress hormones such as cortisol, cortisol is elevated by 800% in MDMA club goers.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).
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.
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?
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).