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

[Rio Fantastic]

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

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 this is indeed the case, 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, since it only works to stop it from being taken up again and doesn't actually cause the initial rate of release to increase? 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)? I'd have assumed that due to the nature of how they work, amphetamine should surely be the more euphoric of the too - the difference between putting a plug in a sink vs turning a tap on, to put it simply so you can see what I'm getting at. I'd love an answer from someone a bit more knowledgeable in neurochemistry/pharmacology than me, as unfortunately as of yet my knowledge on how drugs work is extremely limited to the very bare basics of where they act in the brain and what they feel like when I take them, haha.

Btw mods I wasn't sure if this question was quite "advanced" enough to classify it as being a question for NPD so wasn't sure whether to put it there or BDD, place it where you wish

 

[PotatoMan]

it definitely isn't a basic question lol. it is a very interesting one tho.

homeless -----> N&PD

 

[Rio Fantastic]

it definitely isn't a basic question lol. it is a very interesting one tho.

homeless -----> N&PD

Hahaha I guess not. After reading the threads in this forum though I never feel smart/knowledgeable enough to participate so I never know if what I put here is appropriate. Thanks for taking the decision out of my hands tho

 

[sekio]

Dopamine does not mediate pleasure, it only mediates expectation of reward. I would expect that taking NDRI drugs are going to have better effects when you're in a good mood for the simple reason of "set and setting". But whether or not that's related to dopamine levels in your brain, I couldn't say.

Cocaine is generally reported to be more euphoric than amphetamine because it's actually a triple reuptake inhibitor (blocks reuptake of dopamine, norepinephrine, and serotonin). It's a common misconception that dopamine works alone to provide "euphoria" but the reality is the picture is a lot more complex than the simplifications that get passed around in high school health textbooks. For instance, if you block norepinephrine transporters, MDMA loses a lot of its euphoric/stimulating effects, despite the commonly held knowledge that it's a "serotonin releaser".

This is also why nobody abuses selective serotonin releasing agents - stuff like MDAI seems to be basically a dud when it comes to party drugs. And on the converse, fast-acting releasing agents of all 3 common monoamines (e.g. methylone, methamphetamine, mephedrone) are generally held in high esteem as party-drugs.

There's also suspicion that secondary targets (sigma receptor, TAAR) provide some of the effects/headspace of things like amphetamine and cocaine. I'm not sure how relevant this is, really, though...

 

[PotatoMan]

this is actually close to what i was thinking. a long time ago the question of which euphoria do you prefer came up in my head and i was distinguishing highs on the basis that serotonin and dopamine are the only 2 responsible for euphoria.
then i asked the question before i made a fool of myself on the boards to a mod who made me understand that all of the NTs are what make up a drug's euphoria.

so in your OP you forgot to consider that cocaine affects SE and NE as well. but i also did think that dopamine had a direct effect on euphoria because i attribute it to THC's high. i'm still unsure on what exactly makes us euphoric as sekio and my psych professor mentioned that dopamine is what mediates the expectation or want of a reward. this is prob why the drugs that have a stronger effect on DA make us want to re-dose more.

but like you Rio i never felt confident to participate here and actually feel as though i'm sounding stupid in this post lol.

but after reading sekio's post i wouldn't be upset if i tested my rolls and found methylone, mephedrone or MDMA in them

 

[neurotic]

what you said makes sense... but check out this article's abstract http://www.ncbi.nlm.nih.gov/pubmed/24953830 ... someone brought it up here a while ago

it comes up with the hypothesis that cocaine and methylphenidate psychoactivity is not caused by reuptake inhibition, but rather some other particular interaction with the transporter, which in fact causes dopamine efflux from the neuron, with a mechanism different than amphetamine's, the details are beyond my comprehension though...

this would explain why dopamine reuptake inhibitors such as sibutramine or bupropion don't cause a high like cocaine's.

 

[Rio Fantastic]

Dopamine does not mediate pleasure, it only mediates expectation of reward. I would expect that taking NDRI drugs are going to have better effects when you're in a good mood for the simple reason of "set and setting". But whether or not that's related to dopamine levels in your brain, I couldn't say.

Cocaine is generally reported to be more euphoric than amphetamine because it's actually a triple reuptake inhibitor (blocks reuptake of dopamine, norepinephrine, and serotonin). It's a common misconception that dopamine works alone to provide "euphoria" but the reality is the picture is a lot more complex than the simplifications that get passed around in high school health textbooks. For instance, if you block norepinephrine transporters, MDMA loses a lot of its euphoric/stimulating effects, despite the commonly held knowledge that it's a "serotonin releaser".

This is also why nobody abuses selective serotonin releasing agents - stuff like MDAI seems to be basically a dud when it comes to party drugs. And on the converse, fast-acting releasing agents of all 3 common monoamines (e.g. methylone, methamphetamine, mephedrone) are generally held in high esteem as party-drugs.

There's also suspicion that secondary targets (sigma receptor, TAAR) provide some of the effects/headspace of things like amphetamine and cocaine. I'm not sure how relevant this is, really, though...

I'm a little confused. So dopamine is anticipation of reward rather than the reward itself, you say serotonin may mediate the pleasure response in cocaine but then rightly point out pure serotonin-releasing drugs have no abuse potential, you mention norepinephrine but I mean anxiety attacks are not fun, the fight or flight response isn't fight or flight or fuck yeah I'm really happy, and norepinephrine levels are seven times higher in those going through opiate withdrawals and god knows that isn't a pleasurable state. So the only neurotransmitter we know definitely is involved in pleasure is endorphins? Are you saying that pleasure is just a lot more complex than commonly believed and we really don't know what causes it in the brain, but that it may be dopamine, norepinephrine and serotonin all working together in a way we have yet to understand?? Or those other receptors I've never heard of may be involved?

 

[Rio Fantastic]

this is actually close to what i was thinking. a long time ago the question of which euphoria do you prefer came up in my head and i was distinguishing highs on the basis that serotonin and dopamine are the only 2 responsible for euphoria.
then i asked the question before i made a fool of myself on the boards to a mod who made me understand that all of the NTs are what make up a drug's euphoria.

so in your OP you forgot to consider that cocaine affects SE and NE as well. but i also did think that dopamine had a direct effect on euphoria because i attribute it to THC's high. i'm still unsure on what exactly makes us euphoric as sekio and my psych professor mentioned that dopamine is what mediates the expectation or want of a reward. this is prob why the drugs that have a stronger effect on DA make us want to re-dose more.

but like you Rio i never felt confident to participate here and actually feel as though i'm sounding stupid in this post lol.

but after reading sekio's post i wouldn't be upset if i tested my rolls and found methylone, mephedrone or MDMA in them

I didn't forget cocaine worked on norepinephrine or serotonin, I just (apparently incorrectly) thought the pleasurable, reinforcing effects were mediated by dopamine. I figured the norepinephrine release was responsible for the hyperactivity & excitability and most other side effects, and I thought the effect on serotonin was negligible at best, and that it only released a very low amount when you take very high doses, but perhaps I was incorrect. And hahaha, I don't think we should worry too much about sounding stupid, I've definitely seen people way stupider than us posting on this subforum, what made it worse was they thought they knew they were talking about - at least we know enough to know we know nothing, essentially, you know? haha

 

[Rio Fantastic]

what you said makes sense... but check out this article's abstract http://www.ncbi.nlm.nih.gov/pubmed/24953830 ... someone brought it up here a while ago

it comes up with the hypothesis that cocaine and methylphenidate psychoactivity is not caused by reuptake inhibition, but rather some other particular interaction with the transporter, which in fact causes dopamine efflux from the neuron, with a mechanism different than amphetamine's, the details are beyond my comprehension though...

this would explain why dopamine reuptake inhibitors such as sibutramine or bupropion don't cause a high like cocaine's.

Aha! This may turn out to be a cruical piece of the puzzle and may partially explain this particular mystery. However, my proposition about taking it when you're in a higher dopamine state already giving a better high seems to follow logically, and though I've never tested it, I'm guessing its been tested empirically and isn't true, as I don't get given advice very often to take coke after you've had a satisfying meal to get a better high. Why could this be?

 

[PotatoMan]

So the only neurotransmitter we know definitely is involved in pleasure is endorphins? Are you saying that pleasure is just a lot more complex than commonly believed and we really don't know what causes it in the brain, but that it may be dopamine, norepinephrine and serotonin all working together in a way we have yet to understand?? Or those other receptors I've never heard of may be involved?

this leaves me to believe that the studies about 'marijuana and dopamine' saying that "dopamine is what causes the pleasure" are simply scraping the surface on the direct cause of euphoria?

so what exactly in the weed high causes the euphoria? if weed only affects DA and NE then what can possibly be the reason? not trying to hi-jack the thread rio but now i'm confused aha.
maybe we can just consider those questions rhetorical and leave it at that..

found this study on cocaine for ya rio, unless you've seen it already. they make it clear that the euphoric effects are the least understood but have suggested that it may be because of the sodium blocking effect

 

[Rio Fantastic]

this leaves me to believe that the studies about 'marijuana and dopamine' saying that "dopamine is what causes the pleasure" are simply scraping the surface on the direct cause of euphoria?

so what exactly in the weed high causes the euphoria? if weed only affects DA and NE then what can possibly be the reason? not trying to hi-jack the thread rio but now i'm confused aha.
maybe we can just consider those questions rhetorical and leave it at that..

found this study on cocaine for ya rio, unless you've seen it already. they make it clear that the euphoric effects are the least understood but have suggested that it may be because of the sodium blocking effect

Dude, we should never leave those questions as rhetorical. It's vastly important we find out about the pleasure pathways of the brain, when science has that figured out we can tailor-make the perfect drugs. It's always good to be forever curious and wanting these answers, not just to accept that we don't know and never will. And I'm not fully convinced on the idea that dopamine is purely about motivation and incentive and not linked to the actual pleasure response. For a start, selective typical neurleptics that block solely dopamine have been found to null the pleasurable response to cocaine and methamphetamine, which definitely implies that dopamine is involved in pleasure. There have been several studies done with wireheading - the experimental process where they put an electrode directly on someone's brain - and they put the electrode directly on the ventral tegmental area, the dense group of doapmine neurotransmitters in the brain, and sent a single electrical signal to it, stimulating that part of the brain and, crucially, that part only. Subjects were given a button and could press it at at will, and if the electrode was in certain places they reported a somewhat uncomfortable feeling of wanting more of it but not feeling particularly good. When it was in a different place in the VTA however, the subjects would become elated, start laughing, report a large mood lift, experience a very pleasurable response, even to the point where most of them were unwilling to give the button back, and one man even became violent when they tried to take it off him, I beleive. Interestingly though, one of the most surprising results of the experiment, was that wireheading showed no tolerance. Direct brain stimulation of the pleasure signals in the brain was just as enjoyable the thousandth time as it was the first time, and this was reported across the board. This is actually fantastic news - it means that drug tolerance is a physiological process, something that can be measured and recorded and thus something that hopefully one day can be worked around. This is far more promising than the alternative - that it was a psychologial mechanism, and one will just adjust to any high hey have as they get used to it it will naturally get less pleasurable and more boring. This means that poentially in the future, the drugs they come up with could entirely circumvent tolerance - imagine an MDMA-like drug that was literally exactly as good as the first time, every time!? The possibilities and the potential is incredible. But I'm rambling here - my point is that studies like the one's I've referenced make me believe that dopamine is involved in pleasure - perhaps its down to the subsets of receptors, perhaps most of them are just for anticipation and craving of pleasure and it's just one subset of dopamine receptors that cause the corresponding actual pleasure.

 

[sekio]

you mention norepinephrine but I mean anxiety attacks are not fun, the fight or flight response isn't fight or flight or fuck yeah I'm really happy,

So why do people abuse ethcathinone (selective NE releaser) ? Did you know that methylone is primarily a NE releaser too? The long and short of it is that, as with all things related to mind and body, the fight or flight response is mediated by more than just NE, there is also adrenaline itself... not to mention the effects vary depending on where in the brain or body the NE or adrenaline or dopamine gets released. You're also forgetting excess agonism of dopamine receptors (not NE) is the likely cause of nasty repeptitve tics or compulsive behaviour.

People who are awakened and alert have elevated levels of NE, the mere fact that there's extra NE doesn't immediately mean anxiety is the outcome. Certainly in opioid withdrawal there's other things going on too!

There are certainly many other systems that mediate "feeling good", the serotonergic system is one, the cannabinoid system is another, and the opioid/endorphin system. At some level they all tie into & activate the dopaminergic reward pathways, but through different mechanisms.

If you want a simple explanation, anything that reaches peak concentrations in the brain rapidly and is a release or reuptake inhibitor of NE/DA will be considered euphoric/abusable as a stimulant. Serotonergic compounds like cocaine and MDxx are a more complex euphoria than others but to some extent NE/DA release must be present before it's considered euphoric.

I haven't decided where this puts modafinil, which is supposedly active as a DAT blocker, but very slow onset... I don't think it's "euphoric" even though it's a DRI !

 

[Rio Fantastic]

So why do people abuse ethcathinone (selective NE releaser) ? Did you know that methylone is primarily a NE releaser too? The long and short of it is that, as with all things related to mind and body, the fight or flight response is mediated by more than just NE, there is also adrenaline itself... not to mention the effects vary depending on where in the brain or body the NE or adrenaline or dopamine gets released. You're also forgetting excess agonism of dopamine receptors (not NE) is the likely cause of nasty repeptitve tics or compulsive behaviour.

People who are awakened and alert have elevated levels of NE, the mere fact that there's extra NE doesn't immediately mean anxiety is the outcome. Certainly in opioid withdrawal there's other things going on too!

There are certainly many other systems that mediate "feeling good", the serotonergic system is one, the cannabinoid system is another, and the opioid/endorphin system. At some level they all tie into & activate the dopaminergic reward pathways, but through different mechanisms.

If you want a simple explanation, anything that reaches peak concentrations in the brain rapidly and is a release or reuptake inhibitor of NE/DA will be considered euphoric/abusable as a stimulant. Serotonergic compounds like cocaine and MDxx are a more complex euphoria than others but to some extent NE/DA release must be present before it's considered euphoric.

I haven't decided where this puts modafinil, which is supposedly active as a DAT blocker, but very slow onset... I don't think it's "euphoric" even though it's a DRI !

I'm not claiming that norepinephrine isn't involved in the pleasure response, and I'm agreeing with you that the figuring out the entire physiological mechanism behind a concept as relatively complicated as "pleasure" is indeed difficult, and probably does involve multiple pathways, I just think trying to transfer the overly-simplistic "dopamine hypothesis" of pleasure - i.e. dopamine is the neurotransmitter that mediates pleasure and "feeling good" onto norepinephrine doesn't make it a perfect fit either. I know that your body does plenty of things to conspire to ensure that opiate withdrawal is horrible, but if what you were saying is correct, then surely on top of all the nasty withdrawal symptoms there'd be a distinct euphoria or happiness or some kind of pleasurable feeling associated with it due to the sharp spike in NE levels during.

A quick google search reveals ethcathinione, whilst being active in its own right, also works as a prodrug for methcathinione, which does work on dopamine. Agonism of the dopamine receptor is almost certainly the cause of nasty tics and obsessive, compulsive behaviour, I don't know when I implied that it wasn't. I don't know how you can gloss over the role norepinephrine plays in the fight or flight response - surely, if norepinephrine was soley responsible for the pleasurbale response associated with stimulants, then why on earth would it be the primary neurotransmitter associated with an objectively unpleasant state like fight-or-flight or an anxiety attacK? Why is there no overlap - i.e. if we can assume that the fight-or-flight response is caused by a release of norepinephrine, and we can logically assume that the amount necessary to send you into fight-or-flight "mode" has to be reached by the release of increasing levels of norepinephrine, why isn't the beginning of going into FOF a sense of euphoria or well-being?

Another question I have regarding your theory - it is my understanding beta-blockers block noradrenaline, thus, if your theory was correct, surely beta-blockers should totally inhibit the pleasurable response associated with stimulants, or at least really attenuate them? Now, although many say it is dangerous to combine the two, I have read no reports of people saying it detracted from the enjoyable stimulant experience - in fact, quite the opposite. My google search has revealed that there are many, many anecdotal reports of people using beta-blockers to balance out the side effects of stimulants. If NE was responsible for the euphoria of stimulants, then it's quite unusual people use a drug that blocks NE alongside stimulants? And I haven't read any reports of anyone saying that beta blockers and stimulants are a useless combination that doesn't bring any euphoria.

No offence here, but your simple explanation didn't clarify anything about the idea you've presented that NE is responsible for stimulant euphoria rather than dopamine. You've merely stated what is common knowledge all over Bluelight - literally everyone here thinks that they know the science behind drugs because they're aware meth & coke releases NA and dopamine. that MDMA is serotonin, that heroin is endorphins etc. I'm not saying that I'm any more knowledgeable - I have already confessed I know next to nothing about pharmacology, but that doesn't mean I will instantly defer to your judgement when what you're saying doesn't make sense to me. To clarify, I am really not a stubborn man, I am not the kind of guy who will keep arguing because of my ego, even after I've been convinced that what I'm saying isn't true. I am extremely eager to learn about psychopharmacology as it is a passion of mine, and I beleive this is most likely one of the best ways to learn. Like I said I'm not a dogmatic guy - if I think you're right, I will instantly admit it, and I'm not even saying I think you're wrong, just that it doesn't fully make sense to me at the moment, and I hope I've explained why. As you yourself are an admninistrator, I just hope that you can keep this debate strictly academic and will not feel the need to get personal and offensive. I hope I've managed to show you at least why I'm personally not sold on the theory yet so you can show me where I'm potentailly going wrong. It's a fascinating discussion in my opinion anyhow - I really need to read up on this stuff so I can participate more in this forum.

 

[dopamimetic]

Most beta blockers are designed to work only peripherally and have poor or no ability to cross the blood brain barrier as this would lead to central adverse effects (drowsiness, tiredness, etc.) -> look at clonidine for example. And, but here I'm not that sure, in the brain it's maybe more about alpha-receptors as beta ones. Clonidine indeed has a strong impact on the overall effects of psychostimulants and while it is very NE selective (by agonizing a2 auto receptors, around 80% its potency and 20% is NE-mimetic if I'm right), it was shown to strongly affect dopamine neurotransmission as well. And there are regions in the brain that seem to only have NE transporters that recycle the DA too.

Clonidine lets you sleep while on a decent dose of a psychostimulant, but then again it doesn't completely cancel it out. I've used clonidine many times to counter-act the more disturbing physical side effects of amphetamine / methylphenidate to which I'm very sensible, and - especially when used in combination with a NMDA antagonist, which of course makes things even more complicated - this did work way better than it should have. It's different for everybody probably.

I'm really unsure about the roles of DA, 5-HT, NE etc... somewhat I'd agree to the over-simplification of too much NE = anxiety, tachycardia, paranoia, anorexia - too less DA = anhedonia, low self esteem, anxiety, lack of motivation, but also lack of impulse control, over-sensibility ... - too much DA = stereotypical behavior, aggression, overwhelmed by sensory input / stimuli etc. (stim psychosis being due to NE & DA --> glutamate) - with NE being somewhat wakefulness / energy / jitteriness and DA being motivation / pleasure / self-esteem / control regulation / reward - and 5-HT being very complicated because it has more than 7 subtypes and all that ... also everything is interconnected and related to the relative brain regions and firing patterns etc ...

Endorphins make me really curious. Somehow they would seem to be predicted to tolerance (when looking at anything acting on opioid receptors besides that DAMGO) even more so than dopamine, or at least much more prone to serious rebound / withdrawal effects, but this might not apply to endogenous endorphins(?).

That thing about coke & the possibility that the local anesthetic effect mediates (part) of the euphoria is quite interesting. Somehow it would be known if things like lidocaine or procaine alone would lead to euphoria and I'd say that the pleasure coke addicts experience from snorting lidocaine indeed is more a psychological phenomenon but it can very well be that the channel blocking properties together with sigma agonism contribute a good part to the distinct euphoria. So possibly mixing procaine with fluvoxamine and alpha-PVP could make an interesting cheap coke substitute maybe (don't try that at home!)

 

[Rio Fantastic]

Most beta blockers are designed to work only peripherally and have poor or no ability to cross the blood brain barrier as this would lead to central adverse effects (drowsiness, tiredness, etc.) -> look at clonidine for example. And, but here I'm not that sure, in the brain it's maybe more about alpha-receptors as beta ones. Clonidine indeed has a strong impact on the overall effects of psychostimulants and while it is very NE selective (by agonizing a2 auto receptors, around 80% its potency and 20% is NE-mimetic if I'm right), it was shown to strongly affect dopamine neurotransmission as well. And there are regions in the brain that seem to only have NE transporters that recycle the DA too.

Clonidine lets you sleep while on a decent dose of a psychostimulant, but then again it doesn't completely cancel it out. I've used clonidine many times to counter-act the more disturbing physical side effects of amphetamine / methylphenidate to which I'm very sensible, and - especially when used in combination with a NMDA antagonist, which of course makes things even more complicated - this did work way better than it should have. It's different for everybody probably.

I'm really unsure about the roles of DA, 5-HT, NE etc... somewhat I'd agree to the over-simplification of too much NE = anxiety, tachycardia, paranoia, anorexia - too less DA = anhedonia, low self esteem, anxiety, lack of motivation, but also lack of impulse control, over-sensibility ... - too much DA = stereotypical behavior, aggression, overwhelmed by sensory input / stimuli etc. (stim psychosis being due to NE & DA --> glutamate) - with NE being somewhat wakefulness / energy / jitteriness and DA being motivation / pleasure / self-esteem / control regulation / reward - and 5-HT being very complicated because it has more than 7 subtypes and all that ... also everything is interconnected and related to the relative brain regions and firing patterns etc ...

Endorphins make me really curious. Somehow they would seem to be predicted to tolerance (when looking at anything acting on opioid receptors besides that DAMGO) even more so than dopamine, or at least much more prone to serious rebound / withdrawal effects, but this might not apply to endogenous endorphins(?).

That thing about coke & the possibility that the local anesthetic effect mediates (part) of the euphoria is quite interesting. Somehow it would be known if things like lidocaine or procaine alone would lead to euphoria and I'd say that the pleasure coke addicts experience from snorting lidocaine indeed is more a psychological phenomenon but it can very well be that the channel blocking properties together with sigma agonism contribute a good part to the distinct euphoria. So possibly mixing procaine with fluvoxamine and alpha-PVP could make an interesting cheap coke substitute maybe (don't try that at home!)

That lidocine numbing is insane!! Doubly bizzare since they can't explain why on earth it happens!! I think surely the only reason could be placebo effect - they said in the study they used cocaine addicts, perhaps the cocaine addicts had already taken coke that day or were just so strung out all the time they hardly even got high anymore (similar to how very severe caffeine addicts can't tell for a little while that you've swithced them to decaf) so they got a placebo response as soon as their nose numbed? It's impossibly to say without reading the full study and seeing their exact procedures, its a shame I can't find anything else regarding the study on the internet. It's so bizzare though, I mean, I've had terrible "coke" that had no actual coke in it before, but it made my entire face go numb. At first I was there getting excited cos I thought I was gonna get high, but then....just nothing. Surely, if lidocaine produced the same effect as cocaine then one would expect cocaine to have stopped being produced long ago in lieu of the cheaper, legal and apparently just as effective lidocaine??

 

[dopamimetic]

Yeah, it's strange and just the local anesthetic activity certainly doesn't get one high. I much agree with you that it'll be placebo or anticipated reward from the numbing effect - there are blowheads out there who are so used to shitty cut coke that they dislike pure high-quality stuff because it lacks the instant intense numbing of lidocaine etc. and isn't as pushy as ephedrine or whatever ... this probably also varies greatly between individuals, but for me real cocaine isn't that numbing at all, at least not instantly.. it doesn't burn in the nose and it certainly doesn't numb one's teeth (okay, I don't like to take fucked-up dosages either then).

But it could well be that the channel blocking properties as well as the sigma agonistic effects of cocaine contribute to the overall effects!

I just was interested in what good coke is like, that's why I've tried it out. It's pretty appreciable indeed, but really not worth the price and all the shit associated with global cocaine production, trafficking and consumption. (I can't understand what some people do, act and behave like on coke either, at least partly.. but this applies to many drugs then. I know what it's like to be in full-on mania from 3-MeO-PCP, but this is very disturbing & certainly not achievable with stimulants for me.. and while it is really a borderline experience and certainly nothing for the unexperienced, it would take shitloads even of PCP to turn me into your average antisocial capitalistic psychopath... bold statement, I know )

 

[Rio Fantastic]

Yeah, it's strange and just the local anesthetic activity certainly doesn't get one high. I much agree with you that it'll be placebo or anticipated reward from the numbing effect - there are blowheads out there who are so used to shitty cut coke that they dislike pure high-quality stuff because it lacks the instant intense numbing of lidocaine etc. and isn't as pushy as ephedrine or whatever ... this probably also varies greatly between individuals, but for me real cocaine isn't that numbing at all, at least not instantly.. it doesn't burn in the nose and it certainly doesn't numb one's teeth (okay, I don't like to take fucked-up dosages either then).

But it could well be that the channel blocking properties as well as the sigma agonistic effects of cocaine contribute to the overall effects!

I just was interested in what good coke is like, that's why I've tried it out. It's pretty appreciable indeed, but really not worth the price and all the shit associated with global cocaine production, trafficking and consumption. (I can't understand what some people do, act and behave like on coke either, at least partly.. but this applies to many drugs then. I know what it's like to be in full-on mania from 3-MeO-PCP, but this is very disturbing & certainly not achievable with stimulants for me.. and while it is really a borderline experience and certainly nothing for the unexperienced, it would take shitloads even of PCP to turn me into your average antisocial capitalistic psychopath... bold statement, I know )

Hahaha dude did you post a thread in Reddit about drugs used to approximate mental illness experience? Anyway, I'll say the same thing I said to the guy in that thread - I am bipolar type I, and 3-Meo-PCP is not an approximation of mania, at all, and I have no idea where this rumor came from.

 

[dopamimetic]

No, I haven´t posted a single thing on reddit yet . the net is so full of bullshit .. but there´s certainly something about PCP and mania. I tend to be the dysthymic, unipolar depressed guy & arylcyclohexylamines can and do induce (hypo)mania for me like nothing else, with 3-MeO-PCP being the strongest I know of. It is about some sort of glutamate and dopamine disinhibition / alternated firing patterns .. together with disinhibition of GABAergic inhibition ...

I theorized that there could be an interconnection between mania, psychosis and temporal lobe seizures (as well as depression is common amongst TLS people), but this is far from being proven yet.

Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex.

I´m posting from work now so I don´t have that much time ... (actually I´m on the first day of work again )

 

[sekio]

A quick google search reveals ethcathinione, whilst being active in its own right, also works as a prodrug for methcathinion

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.

Another question I have regarding your theory - it is my understanding beta-blockers block noradrenaline,

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.

 

[Rio Fantastic]

No, I haven´t posted a single thing on reddit yet . the net is so full of bullshit .. but there´s certainly something about PCP and mania. I tend to be the dysthymic, unipolar depressed guy & arylcyclohexylamines can and do induce (hypo)mania for me like nothing else, with 3-MeO-PCP being the strongest I know of. It is about some sort of glutamate and dopamine disinhibition / alternated firing patterns .. together with disinhibition of GABAergic inhibition ...

I theorized that there could be an interconnection between mania, psychosis and temporal lobe seizures (as well as depression is common amongst TLS people), but this is far from being proven yet.

Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex.

I´m posting from work now so I don´t have that much time ... (actually I´m on the first day of work again )

No offence, but if you've never experienced it a true manic episode, how can you make a comment like "there's something about PCP and mania" or make the assertion that a group of drugs induce hypo-mania in you? Reading about mania and hypomania gives the impression it's just like a typical stimulant or something, but they aren't. Unless you know what you're looking out for, telling people you've experienced mania or it makes you manic is totally totally unfounded speculation. I don't meant to be rude here, but appropriating a serious mental illness in order to make your experience appear more "quirky" and interesting than merely being normally high is really insensitive, dude. I know you're not doing this intentionally, it's just I (along with many other bipolar people I've spoken to - among them it's a very common complaint) have a pet peeve of people misusing the phase "bipolar" and what goes along with it - e.g. people who self-diagnose themselves, saying things like "omg, Thursday I was happy, and today I'm sad, im totes bipolar" or "i legit rely have bipolar disorder right one minute i'm in a really good mood then later that day ill be in a sad mood!". Urgh, it really aggravates me, people describing the totally normal continuum of human emotions and describing themselves as "bipolar" because it's the new buzzword or because they want to garner more sympathy than they would just for having normal changes in emotions. Similarly, when you throw term "manic" or "hypomanic" around, despite admitting that you're unipolar/dysthymic and thus have no legitimate manic or hypomanic episodes to compare these highs to, and so are just completely assuming what mania/hypomania is like and appropriating the term just to describe a high. I feel the more people use these terms out of context the more it "dilutes" them, so to speak, and contributes towards people's perceptions of bipolar disorder in a negative way - as something within the realm of normal human experience and therefore controllable, if you see what I'm getting at. I think it can detract from the suffering of those who have to live with bipolar disorder for the rest of their lives by using the terms that specifically reference a very severe, disruptive and even at times life-threatening episode of mental illness and using it to describe your high on a drug just takes away its legitimacy to describe what it originally was intended to describe.

EDIT: On second thoughts, maybe I'm jumping the gun and being a little rash. Why don''t you tell me exactly what your experiences on 3-MeO-PCP felt like (I'm asking for your subjective experiences now dopamimetic, so telling me that 3-MeO-PCP elevates glutamate levels in a similar way to bipolar mania or whatever will be entirely irrelevant to what I'm asking). I want you to tell me exactly what *you* felt on this drug, paying particular attention to elaborate on the specific parts that you would describe as hypomanic or manic.