Dopamine antagonists

[blight12]

This is interesting. I always wondered why its not possible to take a drug that inhibits norepinephrine release with say meth to reduce the negative side effects.

 

[St3ve]

Dopamine does cause euphoria.

Fig 1.

Note that they said that DA release in D3R rich area correlates with amphetamine induced euphoria. Correlation does not necessarily imply causation. The general consensus among neuroscientists is that dopamine does not directly cause pleasure, although it may do so indirectly. Dopamine mainly acts as motivational signal and novelty signal. There are multiple pleasure centres in the brain called "hedonic hot spots" that cause pleasure through mu-opioid receptors, cannabinoid and benzodiazepine receptors. See this paper: http://nro.sagepub.com/content/12/6/500.abstract

 

[specialspack]

Note that they said that DA release in D3R rich area correlates with amphetamine induced euphoria. Correlation does not necessarily imply causation.

Quite....

 

[AlphaMethylPhenyl]

^Its association

Correlation is a number that exists in any statistical comparison

 

[specialspack]

^Its association

Correlation is a number that exists in any statistical comparison

Sorry, your point being..? Perhaps a little is lost in translation - the use of "quite" here is the English exclamation of agreement.

 

[AlphaMethylPhenyl]

He was using the wrong term. Its ok (common mistake). It makes a big difference though, as in saying correlation instead of "high association" is like saying something literally meaningless instead of saying there's a significant association between two variables. Clear enough?

 

[pizzystrizzy]

In general, claims that any of the monoamines 'cause X' without qualification are extreme oversimplications. In the case of dopamine, it has tons of different functions in various different regions and with various different receptors. If it was merely a matter of stimulating dopamine receptors in order to feel good, dopamine agonists would be some of the most abusable drugs in existence, and yet they aren't even slightly fun. Dopamine regulates movement, for example, in a way entirely separate from its effects on mood. There is good reason to believe that the D3 receptor might largely inhibit euphoria. Even with the same receptors, in different parts of the brain the functional result of agonism could be nearly opposite (and I'm not simply referring to autoreceptors vs. post-synaptic receptors). Certainly when dopamine levels get high enough for long enough in a sensitized brain, they directly cause psychosis which is generally not experienced euphorically. Even when the increased dopamine transmission is mediating the positive effects of a drug, in some parts of the brain the subjective feeling is more desire that satiety. So, it is complicated.

All of that said, neuroleptic dopamine antagonists do cause a 'low' of sorts. Not the same kind of low that occurs when you are coming down from a stimulant (indeed, despite your subjective experience, your brain is still flooded with dopamine during that time, but the experience is rather blunted by tachyphylaxis mechanisms). But it is certainly the case that if you take a high dose of a neuroleptic and then subsequently attempt to take a stimulant, it is not going to work very well. Some neuroleptics of course, particularly at low doses (I'm thinking especially of amisulpride here), will block dopamine receptors but preferentially block presynaptic auto-receptors. Others, particularly those in the the atypical class, aren't really occupying a very high percentage of d2 receptors (and tend to dissociate rapidly), while more potently blocking 5ht receptors, some of which (e.g., 5ht-6) are known to magnify the subjective response to dopamine in the nuccleus accumbens when blocked.

Anyway, I could go on, but really my basic point is just that it is a great deal more complicated than "DA = euphoria" or "5ht = happy" and the like... That kind of logic conceals at least as much as it reveals...

 

[ebola?]

Off-topic semantic discussion:

^Its association

Correlation is a number that exists in any statistical comparison

No, a correlation coefficient is a value that may be derived in some statistical comparisons. To say that two variables correlate is to say that they are associated (or more precisely, that changes in one variable are associated with changes in the other).

ebola

 

[AlphaMethylPhenyl]

Actually you're wrong.

In proper statistical terms "association" delineates a reasonable connection between two variables (whether negative or positive, broken down into low, medium, or high), while "correlation" is a number which exists in any statistical comparison.

 

[pizzystrizzy]

Actually you're wrong.

In proper statistical terms "association" delineates a reasonable connection between two variables (whether negative or positive, broken down into low, medium, or high), while "correlation" is a number which exists in any statistical comparison.

Not that this 'debate' really matters, but there is a fair bit of semantic variance when it comes to many statistical terms of art, within a disciplinary tradition but certainly between disciplinary traditions. So it doesn't make a ton of sense to quibble about these matters. As a technical matter, at least in my discipline, the 'number' you just described as "correlation" I would say is rather a 'correlation coefficient.' And two variables can be associated in many different ways besides what you've described (and indeed in ways that are most certainly not correlative), e.g., a u-shaped curvilinear relationship. But I don't really know what the terminology is in other fields...

 

[blight12]

Firstly my thanks for clarifying the definition or correlation. I always thought it referred to that weird stuff that grew on sea floor and now it has been confirmed! While i could spend hours discussing the fascinating world of marine fauna we should probably get back on topic.

So it seems dopamine might not directly result in euphoria or pleasure/reward but might do so indirectly and still possibly in a way where dopamine is the only mechanism as the single cause for this benefit.

This could imply that SNS stimulation might not be required in combination with dopamine for the rec value of stims to result in full effect. So then could it be possible to simply block peripheral stimulation completely to reduce its impact on the side effect profile.

And if this was possible would the effects still be classified as stimulation or is euphoria and reward alone no longer a stimulant without the SNS stimulation. Would this then become a new unique creation as a medium between a depressant and a stimulant? Somehow a depressing stimulant does not sound appealing at all which is probably why this has never become popular?

 

[rickolasnice]

OK I'm lost.. so what causes the euphoria from stimulants?

 

[AlphaMethylPhenyl]

Firstly my thanks for clarifying the definition or correlation. I always thought it referred to that weird stuff that grew on sea floor and now it has been confirmed! While i could spend hours discussing the fascinating world of marine fauna we should probably get back on topic.

haha.

All I know is that whenever someone is class said "correlation", if it didn't correspond to a number, they would get flamed. So I still think its a number.

 

[MeDieViL]

OK I'm lost.. so what causes the euphoria from stimulants?

Its well established mu causes euphoria.

Combined with risperdal wich blocks all da receptors stronger then DA, if i added phenibut all amp euphoria came back completely, da just plays a modulatory role.

In general, claims that any of the monoamines 'cause X' without qualification are extreme oversimplications. In the case of dopamine, it has tons of different functions in various different regions and with various different receptors. If it was merely a matter of stimulating dopamine receptors in order to feel good, dopamine agonists would be some of the most abusable drugs in existence, and yet they aren't even slightly fun. Dopamine regulates movement, for example, in a way entirely separate from its effects on mood. There is good reason to believe that the D3 receptor might largely inhibit euphoria. Even with the same receptors, in different parts of the brain the functional result of agonism could be nearly opposite (and I'm not simply referring to autoreceptors vs. post-synaptic receptors). Certainly when dopamine levels get high enough for long enough in a sensitized brain, they directly cause psychosis which is generally not experienced euphorically. Even when the increased dopamine transmission is mediating the positive effects of a drug, in some parts of the brain the subjective feeling is more desire that satiety. So, it is complicated.

All of that said, neuroleptic dopamine antagonists do cause a 'low' of sorts. Not the same kind of low that occurs when you are coming down from a stimulant (indeed, despite your subjective experience, your brain is still flooded with dopamine during that time, but the experience is rather blunted by tachyphylaxis mechanisms). But it is certainly the case that if you take a high dose of a neuroleptic and then subsequently attempt to take a stimulant, it is not going to work very well. Some neuroleptics of course, particularly at low doses (I'm thinking especially of amisulpride here), will block dopamine receptors but preferentially block presynaptic auto-receptors. Others, particularly those in the the atypical class, aren't really occupying a very high percentage of d2 receptors (and tend to dissociate rapidly), while more potently blocking 5ht receptors, some of which (e.g., 5ht-6) are known to magnify the subjective response to dopamine in the nuccleus accumbens when blocked.

Anyway, I could go on, but really my basic point is just that it is a great deal more complicated than "DA = euphoria" or "5ht = happy" and the like... That kind of logic conceals at least as much as it reveals...

High dose amisulpiride or prochloperazine dont alter amphetamine euphoria at all.

 

[AlphaMethylPhenyl]

Can you cite a source that the mu opiate receptor is responsible for amphetamines euphoria?

Risperidone doesn't block all dopamine receptors strongly; it mostly blocks a1, H1, and D2, with the D1 value being very high. I kind of doubt that's true. Also, you said that phenibut manifested entire amphetamine euphoria after being blocked by Risperidone? I don't know about actual experiments (never-mind anecdotes, but they're not entirely useless), however that just doesn't make sense psycho-pharmacologically. It doesn't agree with your statement on amphetamine euphoria being predicated on mu binding either, as phenibut is clearly GABAergic.

Maybe it would be relevant if you took naloxone (which does block amp euphoria, granted, though not totally), found no high whatsoever, and then noticed phenibut to create a high; as it is I don't really see where you're coming from without a study.

 

[pasha]

Dopamine antagonists, specifically neuroleptic anti-psychotics, down-regulate specific dopamine receptors by up to 60% in chronic usage. I would assume this would apply to some degree in acute dosing also.

Moreover, they cause receptor sensitization in chronic usage, which in theory, should be somewhat the paradox of a dopaminergic comedown. This is where tolerance comes in during anti-psychotic therapy for schizophrenics.

Some people, anecdotally speaking, enjoy consuming anti-psychotics prior to an amphetamine binge. This could explain why in clinical trials, co-administration of amphetamine with anti-psychotics yielded decent results.

 

[Hammilton]

Can you cite a source that the mu opiate receptor is responsible for amphetamines euphoria?

I'm not going to bother finding the source for you, but there have been many studies which find the euphoric effects of amphetamine are dependent upon the ability of opioid receptors to function. block them with naloxone, self administration stops.

 

[Gaius]

Local mu and delta opioid receptors regulate amphetamine-induced behavior and neuropeptide mRNA in the striatum. [PubMed]

The purpose of this study was to investigate the role that mu and delta opioid receptor blockade has upon stimulant-induced behavior and neuropeptide gene expression in the striatum. Acute administration of amphetamine (2.5 mg/kg i.p.) caused an increase in behavioral activity and preprodynorphin, substance P, and preproenkephalin mRNA expression. Intrastriatal infusion of the mu opioid antagonist, H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), or the delta opioid antagonist, H-Tyr-Tic[CH(2)NH]-Phe-Phe-OH (TIPPpsi), significantly decreased amphetamine-induced vertical activity. However, only CTAP reduced amphetamine-induced distance traveled. Quantitative in situ hybridization histochemistry revealed that CTAP blocked amphetamine-induced preprodynorphin and substance P mRNA. However, preproenkephalin mRNA levels in the dorsal striatum were increased to the same extent by CTAP, amphetamine, or a combination of the two drugs. In contrast, TIPPpsi significantly decreased amphetamine-induced mRNA expression of all three neuropeptides. These data indicate that both mu and delta receptor subtypes differentially regulate amphetamine-induced behavior and neuropeptide gene expression in the rat striatum.

Dopamine or opioid stimulation of nucleus accumbens similarly amplify cue-triggered 'wanting' for reward: entire core and medial shell mapped as substrates for PIT enhancement.[PubMed]

Pavlovian cues [conditioned stimulus (CS+)] often trigger intense motivation to pursue and consume related reward [unconditioned stimulus (UCS)]. But cues do not always trigger the same intensity of motivation. Encountering a reward cue can be more tempting on some occasions than on others. What makes the same cue trigger more intense motivation to pursue reward on a particular encounter? The answer may be the level of incentive salience ('wanting') that is dynamically generated by mesocorticolimbic brain systems, influenced especially by dopamine and opioid neurotransmission in the nucleus accumbens (NAc) at that moment. We tested the ability of dopamine stimulation (by amphetamine microinjection) vs. mu opioid stimulation [by d-Ala, nMe-Phe, Glyol-enkephalin (DAMGO) microinjection] of either the core or shell of the NAc to amplify cue-triggered levels of motivation to pursue sucrose reward, measured with a Pavlovian-Instrumental Transfer (PIT) procedure, a relatively pure assay of incentive salience. Cue-triggered 'wanting' in PIT was enhanced by amphetamine or DAMGO microinjections equally, and also equally at nearly all sites throughout the entire core and medial shell (except for a small far-rostral strip of shell). NAc dopamine/opioid stimulations specifically enhanced CS+ ability to trigger phasic peaks of 'wanting' to obtain UCS, without altering baseline efforts when CS+ was absent. We conclude that dopamine/opioid stimulation throughout nearly the entire NAc can causally amplify the reactivity of mesocorticolimbic circuits, and so magnify incentive salience or phasic UCS 'wanting' peaks triggered by a CS+. Mesolimbic amplification of incentive salience may explain why a particular cue encounter can become irresistibly tempting, even when previous encounters were successfully resisted before.

Reward Processing by the Opioid System in the Brain

Opioid peptides and receptors are expressed through out the reinforcement network, placing the opioid system in a key position to modulate this circuit. Experimental data have accumulated over nearly 50 years showing that the opioid system is involved with reinforcement processes. Globally, systemic mu and, to a lesser extent, delta agonists produce positive reinforcement, whereas kappa agonists induce aversion, hallucinations, and malaise. Conversely, mu and delta antagonists suppress the positive reinforcing properties of natural rewards and opiate or nonopioid drugs, whereas kappa antagonists facilitate these effects... Many different modalities of chronic cocaine or psychostimulant treatment have been used to investigate the regulation of opioid receptor expression. Generally, literature in the field suggests an increase in mu receptor gene expression in several brain structures. Levels of mu receptor mRNA were increased in the NAc and rostral cingulate cortex after chronic exposure to cocaine or after cocaine CPP... Chronic exposure to amphetamine increased mu receptor gene expression in the rostral CPu and decreased the expression in the shell of the NAc (393). In the FrCx, mRNA levels for mu receptors were increased or not modified depending on the protocol of drug administration, using a cocaine CPP (210) or chronic binge ( 18 ) paradigm, respectively... Several groups investigated the effects of withdrawal from cocaine or amphetamine on mu receptor transcription and observed either an increase or no change in mRNA levels. Mu receptor mRNA levels were increased in the FrCx after cocaine withdrawal ( 18 ) and in the VTA following withdrawal from amphetamine

From here. This paper seems to be the best source of condensed information about this.

I guess that last one also helps to explain the phenomena whereby people often find something more rewarding after their initial exposure.

 

[AlphaMethylPhenyl]

Good info. I dont doubt it, just was told by a pharmacist that it primarily had to do with a directly dopaminergic mechanism.

 

[Gaius]

Well as far as I can tell, those papers do in fact single out dopaminergic pathways integrated with the opioid system as the primary cause for the wanting/reinforcement. The last paper doesn't mention norepinephrine at all, so I'd have to do some more digging to find something satisfying regarding that aspect.