Would a D1/D5 receptor full agonist have recreational properties?

[serotonin2A]

I'm not denying Berridge et al.'s theories about dopamine relating to incentive salience and motivation and what not, but I also can't deny the evidence that pharmacological increases in global dopamine signaling produce euphoric responses in humans.

How else can you explain euphoric reactions to high dose d-amph?

I'm not saying that dopamine doesn't play a role in reward but the situation isn't as simple as dopamine = euphoria. Dopamine seems to be more involved in reward prediction, and possibly in minimizing prediction errors, then in mediating reward. It had also been argued that dopamine is involved in determining salience. It's complicated by the fact that there are multiple dopamine receptors and multiple central pathways.

Amphetamine and methamphetamine release norepinephrine more strongly than they release dopamine. Studies in humans have shown that a high dose of the dopamine antagonist pimozide does not block the rewarding effects of d-amphetamine, but the effects are strongly attenuated by the NET inhibitor atomoxetine. So norepinephrine appears to play a role in the "euphoria" produced by amphetamine.

 

[endotropic]

Amphetamine and methamphetamine release norepinephrine more strongly than they release dopamine. Studies in humans have shown that a high dose of the dopamine antagonist pimozide does not block the rewarding effects of d-amphetamine, but the effects are strongly attenuated by the NET inhibitor atomoxetine. So norepinephrine appears to play a role in the "euphoria" produced by amphetamine.

So based on that data (and first hand reports with atomoxetine) we know that selective NET inhibitors don't produce euphoria, while on the other hand NET/DAT double inhibitors like MDPV do produce euphoria.

Also keep in mind that pimozide is a potent D2/3/4 antagonist, with essentially no affinity for D1/5. I still think Occam has my back on this one.

 

[serotonin2A]

So based on that data (and first hand reports with atomoxetine) we know that selective NET inhibitors don't produce euphoria, while on the other hand NET/DAT double inhibitors like MDPV do produce euphoria.

Also keep in mind that pimozide is a potent D2/3/4 antagonist, with essentially no affinity for D1/5. I still think Occam has my back on this one.

In response to your point about atomoxetine not producing euphoria, keep in mind that selective DAT inhibitors like GBR12909 produce sedation in humans, not psychostimulant effects. So it doesn't seem like agents that selectively inhibit either NE or DA uptake are euphoric. But trying to compare amphetamine and atomoxetine is like comparing apples and oranges, because atomoxetine doesn't release norepinephrine. There are PK reasons why GBR may not be euphoric, but they would apply equally to atomoxetine, so bringing up evidence with uptake inhibitors gets us nowhere.

Second, it is important to keep in mind that I didn't say that norepinephrine is the primary mediator of amphetamine-induced euphoria, I said that it appears to play an important role. It could be that a combination of effects on norepinephrine and dopamine is necessary. That may be why all the abused psychostimulants hit both DA and NE. But the fact is that there is no evidence that amphetamine induces euphoria solely by activating dopamine receptors.

Third, your argument with pimozide would hold water if atomoxetine didn't block the effect of amphetamine, but why would it block the response to amphetamine if it is only mediated by D1/5 receptors?

If dopamine receptor activation = euphoria, then dopamine agonists such as lisuride and bromocriptine should be subject to abuse. They are not. And why is dopamine release more associated with drug craving then with drug-induced euphoria?

At the moment there is no evidence that amphetamine induces euphoria in humans only through dopamine release. If you can cite some studies that show that, please do so. But so far you haven't included any evidence to back up that claim.

 

[endotropic]

In response to your point about atomoxetine not producing euphoria, keep in mind that selective DAT inhibitors like GBR12909 produce sedation in humans, not psychostimulant effects. So it doesn't seem like agents that selectively inhibit either NE or DA uptake are euphoric. But trying to compare amphetamine and atomoxetine is like comparing apples and oranges, because atomoxetine doesn't release norepinephrine. There are PK reasons why GBR may not be euphoric, but they would apply equally to atomoxetine, so bringing up evidence with uptake inhibitors gets us nowhere.

I was comparing atomoxetine to MDPV, not to amphetamine. The point I was making was atomoxetine=NET inhibitor=no euphoria, MDPVAT/NET inhibitor=euphoria. The major difference between the two is the dopamine reuptake inhibition.

GBR12909 increases dopamine very slowly and modestly compared to a drug like MDPV (or cocaine), so much so that it actually inhibits cocaine induced increases in extracellular dopamine. That said I don't think it's a very good compound to judge how selectively increasing extracellular dopamine relates to euphorogenic effects.
http://www.ncbi.nlm.nih.gov/pubmed/1839568

Atomoxetine actually increases extracellular norepinephrine with a similar time course and a greater maximal effect than the double reuptake inhibitor methylphenidate (an abusable drug), so I still think it's a valid comparator.
http://www.ncbi.nlm.nih.gov/pubmed/20403082

Second, it is important to keep in mind that I didn't say that norepinephrine is the primary mediator of amphetamine-induced euphoria, I said that it appears to play an important role. It could be that a combination of effects on norepinephrine and dopamine is necessary. That may be why all the abused psychostimulants hit both DA and NE. But the fact is that there is no evidence that amphetamine induces euphoria solely by activating dopamine receptors.

No argument here. Combined transporter inhibition might be key for a number of reasons, including the fact that NET rapidly clears dopamine in addition to norepinephrine, and that inhibition of either DAT or NET alone has almost no effect on extracellular dopamine
http://www.ncbi.nlm.nih.gov/pubmed/11150317

Third, your argument with pimozide would hold water if atomoxetine didn't block the effect of amphetamine, but why would it block the response to amphetamine if it is only mediated by D1/5 receptors?
If dopamine receptor activation = euphoria, then dopamine agonists such as lisuride and bromocriptine should be subject to abuse. They are not. And why is dopamine release more associated with drug craving then with drug-induced euphoria?

My point with pimozide was that their still might be hope for D1/5 agonists, like OP suggested. Both of the other compounds you listed are D2/3/4 agonists.

At the moment there is no evidence that amphetamine induces euphoria in humans only through dopamine release. If you can cite some studies that show that, please do so. But so far you haven't included any evidence to back up that claim.

I can't back that up because I'm not making that claim. This is the only point I'm really trying to make in this thread:

pharmacological increases in global dopamine signaling produce euphoric responses in humans.

My point being I still don't think we should write off D1/5 agonists too quickly.

 

[St3ve]

I'm not denying Berridge et al.'s theories about dopamine relating to incentive salience and motivation and what not, but I also can't deny the evidence that pharmacological increases in global dopamine signaling produce euphoric responses in humans.

How else can you explain euphoric reactions to high dose d-amph?

Dopamine and noradrenaline primarily affect the older midbrain structures in the brain. In terms of input it goes: external stimulus->sensory cells-> brain stem sensory areas->cerebral sensory areas->midbrain processing->cortical processing. This is an extremely linear oversimplification, but will suffice for what I'm trying to explain. The main nuclei in the brain that use dopamine as a neuromodulator are divided into four main pathways. The mesolimbic pathway is probably the most relavent one in terms of recreational drug effects. Mesocortical pathway is involved in affecting decision making and salience as welll as explaining some of the behavioural changes. It's also involved in pathlogical states like schizophrenia and psychosis. The negrostriatal one affects motor control (as seen in parkinson's disease which is characterised by negrostriatal dopamine neurons dying. Then the last one, tuberoinfundibilar pathway affects the release of certain hormones.

Noradrenaline release originates from the locus coeruleus in the brain stem. It hits a number of different areas in the brain. I'm not as familiar with all of its roles, but it seems to broadly be involved in states related to fight or flight type responses. This can include amygdala based emotions related to fear, or switches towards a more alert and vigilant state cognitively. Noradrenaline can also affect the "gain" on sensory input, like making sound be perceived as louder, or colours as more intense.

Dopamine and noradrenaline appear to primarily affect brain areas that are more downstream in terms of brain pathways. Subjective experience is more likely characterised by upstream neocortical activity. It's the interpretation of the higher brain areas that determine how midbrain input is perceived. Dopamine and noradrenaline essentially only serve to cause a switch in state of awareness, the neocortical areas integrate this information together with input from other areas in the brain to build up a percept of what's happening externally and internally.

Saying that x amount of dopamine = fun, or x amount of noradrenaline + dopamine = fun is too simple. It depends on which pathways and brain structures are being affected by this change in neuromodulatory action and how they affect the integration by the neocortex that determine what we perceive.

A simple example is that of a rollercoaster ride. Some people find it fun and some find it awful. Essentially all that is happening in terms of neuromodulators is an adrenaline rush. Fast unexpected motions, potentially lethal pathways, strong physical sensations will active the amygdala and cause a fight or flight response. Depending on the interpretation of the individual this can be perceived as terrifying, or they can reject the midbrain input knowing they are safely strapped in, "let go", and enjoy the thrill of the ride.

Then I should point out that there's a lot of feedback communication between higher brain areas and lower brain areas as well. In this way, people prone to feeling worried, overthinking things, anxiety, paranoia, etc. Will more likely react more sensitively to amphetamine and be more prone to experiencing negative effects instead of euphoria, due to their predisposed disposition towards midbrain related input. Similarly those with a more free flowing personality, inclined towards action, will most likely perceive the extra dopamine and noradrenaline as exciting and euphoric.

Natural dopamine and noradrenaline activity reflect a change in external environment (stimuli) that then cause a change in the internal environment.Endogenous opioate release are is dependent on changes in the internal environment, and mostly affect counter changes in the internal environment.

In that sense, mu-opioid receptor binding sends a much more direct message of "goooooooooood" to the brain, that is much less open to interpretation compared to the externally dependent midbrain dopamine/noradrenaline messages.

 

[serotonin2A]

If you go back and read the question I answered above was about how amphetamine works, not about MDPV.

But if selective DA drugs don't induce euphoria and psychostimulants only induce euphoria because they have mixed DA/NE effects, then why would you think that a selective D1/5 agonist would be euphoric?

One question that I think should be asked is why you would say that you are hoping not to write off D1/5 receptors? It is one thing to wonder about whether D1/5 agonists have recreational potential, but to actually hope that is the case is frankly a bit annoying. Why would that be a good outcome? So that RC distributors can identify another class of abused substances that can be sold over the internet? That will just prevent any D1/5 agonists from being developed as medicines when they potentially could help people. Luckily, the selective D1 agonists that are in development don't seem to produce euphoria.

I understand we are discussing this on a website devoted to recreational drug use, but I think some people who visit this site need to consider how much collateral damage the recreational drug scene can potentially do to pharmacology research. I don't think that this is a viewpoint that is represented here enough. I know that some people here have called for some self censorship to prevent things from escaping onto the RC market, but the fact that some approach the study of pharmacology only as a search for new ways to get high is just as much of a problem. The level of damage that the recreational drug scene has done, by causing tool compound after tool compound to be controlled, is incredibly large. There are many interesting studies that will never be performed. And the real shame is that many of those compounds are not all that useful as recreational substances. If you hope that D1/5 compounds are recreational, than you are also hoping that they will never be developed into therapeutic drugs, and that they will be difficult for obtain for scientific studies.

 

[endotropic]

I don't hope for things to be one way or the other, I just want to know the truth. If the truth is that D1/5 receptor agonists are recreational drugs then I don't want that possibility to be written off because dogma says that dopamine = incentive salience and pleasure has nothing to do with it. I would be just as happy to find out that D1/5 agonists make you feel terrible as long as I have a concrete answer (although I suspect that won't be the case).

It's an unfortunate political reality that we have to avoid enjoyable drugs in drug discovery, but as a scientist I don't really give a damn. Maybe we should concentrate on what types of policies and mindsets need to be changed so that we can discuss drugs more rationally, rather than what findings we might have to suppress to appease the prohibitionists.

You can find old posts of mine where I discourage people from using unscheduled research compounds with traditional mechanisms of action for the exact reasons you mentioned above. I don't think there's anything to learn from abusing MK-801 for example. But when we're talking about a drug whose expected effects are largely unknown in man? I honestly think the entire scientific and medical community can benefit from the knowledge of what that drug did in that case. Chemists have been taste testing their own creations since the dawn of chemistry, and the results of those tests used to be considered valuable information. I think we've lost a lot by rejecting that practice (although we've probably saved a few chemists).

But if selective DA drugs don't induce euphoria and psychostimulants only induce euphoria because they have mixed DA/NE effects, then why would you think that a selective D1/5 agonist would be euphoric?

I can show you numerous cases where healthy people found high dose L-dopa pleasurable, and I'm not convinced GBR affects extracellular dopamine enough to really address the question. I've been trying to find a selective dopamine releaser for a while now, because I don't think anything else will settle this question convincingly.

Saying that x amount of dopamine = fun, or x amount of noradrenaline + dopamine = fun is too simple. It depends on which pathways and brain structures are being affected by this change in neuromodulatory action and how they affect the integration by the neocortex that determine what we perceive.

But is it as simple as drugs that increase dopamine signaling throughout the entire brain are fun? I'm not convinced that's not the case yet - and yes I realize that's not a popular theory these days.

 

[serotonin2A]

I don't hope for things to be one way or the other, I just want to know the truth. If the truth is that D1/5 receptor agonists are recreational drugs then I don't want that possibility to be written off because dogma says that dopamine = incentive salience and pleasure has nothing to do with it. I would be just as happy to find out that D1/5 agonists make you feel terrible as long as I have a concrete answer (although I suspect that won't be the case).

It's an unfortunate political reality that we have to avoid enjoyable drugs in drug discovery, but as a scientist I don't really give a damn. Maybe we should concentrate on what types of policies and mindsets need to be changed so that we can discuss drugs more rationally, rather than what findings we might have to suppress to appease the prohibitionists.

That's not really what I'm talking about. I'm not worried that D1 agonists will be enjoyable because our society has a mindset against drugs that are fun. When you work in CNS pharmacology you know that some drugs will make people fell good. In fact, that's the whole reason why any benzodiazepine agonists are made. I'm worried about D1 agonists being enjoyable because that would probably severely limit their usefulness as treatments for schizophrenia and Parkinson's disease. Based on how prone schizophrenia patients are to use nicotine compulsively, trying to treat them with a D1 agonist with reinforcing effects could be extremely problematic. The same might be true for Parkinson's patients, who are already prone to compulsive activities. Luckily, IV or SC administration of the selective D1 agonist dihydrexidrine doesn't seem to be all that reinforcing in humans, at least in the preliminary studies to date.

You can find old posts of mine where I discourage people from using unscheduled research compounds with traditional mechanisms of action for the exact reasons you mentioned above. I don't think there's anything to learn from abusing MK-801 for example. But when we're talking about a drug whose expected effects are largely unknown in man? I honestly think the entire scientific and medical community can benefit from the knowledge of what that drug did in that case. Chemists have been taste testing their own creations since the dawn of chemistry, and the results of those tests used to be considered valuable information. I think we've lost a lot by rejecting that practice (although we've probably saved a few chemists).

I think you have to differentiate the use of these compounds in a way that is informative versus what most people are actually doing. It is incredibly interesting to understand what a drug like MK-801 does to someone. Unfortunately, most of the time when people try to characterize the effects of a drug like that, they do it in a way that is either worthless or is actually detrimental. Buying a compound off the internet and taking it isn't research, because the knowledge it reveals is worthless. How do you know what you are taking? Think about the Ricaurte incident where they received mislabled MDMA. If RTI can't even get it right all the time, then how can you expect some guy in his basement with no chemical training and no analytical equipment to do a better job? And even if you have the substance you are taking chemically analyzed, that still doesn't mean that your experience is relevant to anyone else. A few years back, when bromo-dragonfly was more common, there were conflicting potency claims that were made. So instead of being informative, the so-called "research" that all those people did actually made the pharmacology of bromo-dragonfly more confusing.

In terms of what you said about scientific curiosity about the effects of a drug that are unknown to man, I would argue that selective D1 agonists ARE being tested in man, in clinical trials. You can read papers about what dihydrexidrine does to people.

I can show you numerous cases where healthy people found high dose L-dopa pleasurable, and I'm not convinced GBR affects extracellular dopamine enough to really address the question. I've been trying to find a selective dopamine releaser for a while now, because I don't think anything else will settle this question convincingly.

With L-DOPA, it's not really all that informative because it's also a precursor to norepinephrine, so that doesn't really help to clarify the issue. I agree that GBR has some issues that make it a poor ligand. But I've been trained to be skeptical, and at the moment I don't see any evidence that activating dopamine receptors alone is sufficient to produce pleasurable effects in humans. On the other hand, there is a lot of evidence that at least under certain conditions dopamine release is actually associated with dysphoria.

 

[AlphaMethylPhenyl]

I thought D1 agonists were being tested for the cognitive symptoms of schizophrenia...might be wrong tho.

 

[St3ve]

D1/D5 (there's no selective D1 or D5 agonist) agonists should act as memory enhancers of some sort. D1/D5 receptor activation in the hippocampus is needed to induce the late phase of LTP (early LTP can occur without D1/D5 activity) (see Lisman et al 2011 for extensive review). Without D1/D5 activity LTP simply fades after a few hours, some animal models show that this is reflected in behavioural memory tests as well. You'd then expect that extra dopamine activity would increase L-LTP (or long term memory) as well. There's some limited evidence out there suggesting this is the case, but it's pretty limited. L-DOPA has shown to improve memory deficits in Parkinson's disease and alzheimer's disease models. It also improved word learning in humans. As far as I'm aware though, no one has ever tested whether D1/D5 agonists actually improve memory in humans.

 

[AlphaMethylPhenyl]

The thing about this thread is that people aren't thinking very far...

Ask anyone who's on a high dose of a nueroleptic and stimulant if their memory has improved. Gather data. Make conclusion.

 

[ebola?]

Ask anyone who's on a high dose of a nueroleptic and stimulant if their memory has improved.

These data don't sound particularly reliable.

ebola

 

[AlphaMethylPhenyl]

A bit simplified but you get the picture (i.e. rigorous statistical method was implicit). Feel free to respond.

 

[ebola?]

Personal observations of one's cognitive efficacy tend to be unreliable and invalid, often having much more to do with affect.

ebola

 

[AlphaMethylPhenyl]

Oh I see. Righto. Test them then?

 

[specialspack]

Why would it be worthless? I don't think amphetamines euphoria is related to an increase in norepinepherine. But maybe it's the dopamine increase along with the TAAR agoinism (which just in turn releases more dopamine & norepinepherine) & MAOI activity? And here I'm talking about direct dopamine agonism which would most likely reduce sysnaptic levels of dopamine.

Well, we know that blocking norepinepherine release makes MDMA much less fun (Hysek et al 2011). I don't think anyone has done a study giving a NET blocker and amphetamine at the same time?

And anecdotal reports seem to suggest that ethylphenidate (pretty pure DAT) is less pleasant than methlyphenidate (mixed DAT and NET).

 

[St3ve]

Well, we know that blocking norepinepherine release makes MDMA much less fun (Hysek et al 2011). I don't think anyone has done a study giving a NET blocker and amphetamine at the same time?

And anecdotal reports seem to suggest that ethylphenidate (pretty pure DAT) is less pleasant than methlyphenidate (mixed DAT and NET).

Because of Roy Wise's theory on dopamine being the pleasure neurotransmitter, everyone has sort of ignored the role noradrenaline plays in drug abuse. Dopamine has been in the spotlight for over 30 years now, and the myth that it's the "pleasure" neurotransmitter is still being spread on all sorts of layman websites. Mr Wise himself doesn't even think dopamine is the source of pleasure anymore! Same with low levels of serotonin being the cause of depression, another myth that is still being spread, but that's a whole other sandwich...



The "pleasure" thing itself I think has very little to do (directly at least) with the amount of DA or NA being released. As I tried to explain before, these things happen in the "middle" of the brain's overall signalling pathway. They are neuroMODULATORS and serve to signal a change in environmental circumstances. Dopamine attaches "salience" or importance to an otherwise bland/ignorable stimulus, giving that stimulus priority to reaching conscious awareness.This attaching of salience or importance to things seems to extend to memory as well. Dopamine release appears to be (or at least one of) the factors that decides what information is to be stored for a long time, and which information was not important enough and can be scheduled for deletion after a short time. By adding salience to stimuli, dopamine also acts as a motivator. There's many, many papers out there that observe increased dopamine signalling in response to reward predicting cues (as well as aversive ones, mind). Moreish drugs tend to also have a dopamine heavy component, giving you a nearly uncontrollable urge to take more. Not necessarily because it's fun, but because you feel the NEED to do so. One of Berridge's papers show that hyperdopaminergic mice did not respond to reward more than their genetically unaltered control mice, but they did show increased desire/effort to obtain the reward.

Noradrenaline on the other hand comes from an even older part of the brain. All noradrenaline release in the brain originates from the locus coeruleus (LC). The general idea here is that it acts as a master "ON" switch in the brain. For example, neurons in the LC are completely inactive during sleep and fire tonically at a low rate during awake hours. This is why stimulants acting on noradrenaline can keep you awake for hours and hours. They switch to rapid burst firing mode in response to arousing stimuli. The LC projects to a huge amount of areas in the brain, including those involved in sensory processing and reward. Burst firing in the LC is thought to cause a switch from default mode network activity to the task-positive network activity. In basic terms it switches you from being in a relaxed and disengaged state (thining about the past/future, re-evaluating your thoughts and feelings) to being alert and involved in actively doing something (ranging from having simple conversation, to being under severe stress on the battlefield, to having sex).

There's a large overlap in the target areas that DA and NA innervate, this suggests that they are intimately involved in fine tuning responses in the brain. Both of them are increasingly active to both pleasurable and non-pleasurable events. This is their "job", they make sensory input "special" by attaching salience, desire, fear, emotion and other labels to it. Neither NA or DA are exclusively positive in the labels they can attach. The higher areas in the brain integrate the "sum" of what a very finely-tuned DA/NA signalling combo is telling it about sensory input.

Something like amphetamine merely acts as a rough amplifier of all DA and NA modulation. It is up to the individual to interpret what this means. Amphetamine can cause feelings of fun and excitement in response to external stimuli. As in music that normally sounded "interesting" may now sound absolutely "amazing". A mild desire to have sex at some point maybe, can turn into a several hour long porn-watching wankathon. Similarly a loud noise outside while you are reading stuff on the internet may cause you to jump up and quickly look (noradrenaline burst). While under amphetamines that same loud noise will make you feel more like you just literally shat yourself (noradrenaline gigaburst). Soberly you might walk through the kitchen and notice that ever growing stash of dishes and think "oh I should really clean them at some point" (dopamine burst). In an amphetamine fueled hyperdopaminergic state this might become "if I don't clean these motherfucking dishes right now, the whole world is gonna end" (dopamine gigaburst).

I don't think there is anything inherently pleasurable by increased DA or NA signalling. It's entirely dependent on circumstances that makes things like amphetamines fun. Sitting on the couch doing nothing while high on amphetamines does not make me feel euphoric in the slightest, quite the contrary really. I feel edgy, panicky and worried unless I'm actively engaged in doing something. The increased motivation amphetamines cause means you'll complete more "tasks" leading to more feelings of natural reward. Dopamine burst firing in terms of reward prediction has also been shown to be somewhat proportional, as in larger dopamine bursts predict more reward. It's possible that increased perceived potential reward for cleaning the dishes on amphetamine will actually lead to a larger feeling of reward once the task is complete. Successfully completing tasks in turn then leads to more dopamine release which will further motivate you to complete other tasks.

 

[endotropic]

I don't think there is anything inherently pleasurable by increased DA or NA signalling. It's entirely dependent on circumstances that makes things like amphetamines fun. Sitting on the couch doing nothing while high on amphetamines does not make me feel euphoric in the slightest, quite the contrary really. I feel edgy, panicky and worried unless I'm actively engaged in doing something. The increased motivation amphetamines cause means you'll complete more "tasks" leading to more feelings of natural reward. Dopamine burst firing in terms of reward prediction has also been shown to be somewhat proportional, as in larger dopamine bursts predict more reward. It's possible that increased perceived potential reward for cleaning the dishes on amphetamine will actually lead to a larger feeling of reward once the task is complete. Successfully completing tasks in turn then leads to more dopamine release which will further motivate you to complete other tasks.

Clinical trials don't really bear that out though. They show "drug liking" effects, "subjective drug high", etc., at the same dose ranges (if not lower) that people use recreationally. So unless you think something about the research environment is intrinsically rewarding then the pleasurable effects have to be intrinsic to the drug.

I've been getting private message reports from people that have used high dose D1/5 agonists. Hopefully someone decides to come forward publicly, the results sound interesting.

 

[St3ve]

Clinical trials don't really bear that out though. They show "drug liking" effects, "subjective drug high", etc., at the same dose ranges (if not lower) that people use recreationally. So unless you think something about the research environment is intrinsically rewarding then the pleasurable effects have to be intrinsic to the drug.

I've been getting private message reports from people that have used high dose D1/5 agonists. Hopefully someone decides to come forward publicly, the results sound interesting.

Have you got refs for those clinical trials? I'd like to see what the subjects were allowed to do whilst high on these substances. There could be things about the research environment that could be considered as intrinsically rewarding. A researcher asking someone on speed what they are feeling will motivate the subject to start conversing with the researcher and hence trigger social reward. One of my favourite activities to do on speed and other stims is to rant to other people about anything and everything that comes to mind...I really doubt anyone who's kept in total isolated from others, and has nothing to entertain themselves with whilst high on amphetamines or some other dopaminergic compound, will be able to rate the experience as 100% enjoyable. They'll still have their thoughts though, and the thought changes induced by dopaminergics could be considered as pleasurable... I don't think there's a definitive way to say dopamine = pleasure yes or no.

There is however some evidence that things like cannabis or heroin are much more intrinsically rewarding than dopaminergic compounds as they directly stimulate hedonic hotspots (neural correlates for the sensation of pleasure itself).

 

[endotropic]

Have you got refs for those clinical trials? I'd like to see what the subjects were allowed to do whilst high on these substances. There could be things about the research environment that could be considered as intrinsically rewarding. A researcher asking someone on speed what they are feeling will motivate the subject to start conversing with the researcher and hence trigger social reward. One of my favourite activities to do on speed and other stims is to rant to other people about anything and everything that comes to mind...I really doubt anyone who's kept in total isolated from others, and has nothing to entertain themselves with whilst high on amphetamines or some other dopaminergic compound, will be able to rate the experience as 100% enjoyable. They'll still have their thoughts though, and the thought changes induced by dopaminergics could be considered as pleasurable... I don't think there's a definitive way to say dopamine = pleasure yes or no.

I was referring in general to studies like this one that use a multi-item questionnaire to assess liking.

There is however some evidence that things like cannabis or heroin are much more intrinsically rewarding than dopaminergic compounds as they directly stimulate hedonic hotspots (neural correlates for the sensation of pleasure itself).

You can also find evidence from microdialysis studies that those compounds increase extracellular dopamine levels in relevant brain regions.