non-reinforcing psychostimulants and opioids

[DotChem]

Metabotropic Glutamate Receptors type 5 (mGluR5)-null mice do not show any reinforcing effects with neither opioids (heroine) or psychostimulants(methamphetamine, cocaine). In other words, mGluR5-null phenotype do not exhibit opioid or cocaine induced conditional place preference. Correct me if I am wrong!!

My question is: do opioids and psychostimulants also produce "euphoria" and other NAcc mediated effects of OPs/STIMS in mGluR5-null mice without the reinforcing present in the wild-type mice? If that would be the case, then would addition of a mGluR5 antagonist to an opiate or a stim provide both potentiation of Nacc-mediated "reward" effect of OP and Stims without the reinforcing??

MGluR5, iirc is also involved in memory consolidation, learning and perception. So the question is: does mGluR5 antagonism prevent the consolidation ot the "memory of the experience" of euphoria associated with Nacc DAergic activation? So the brain can still have good time but don't make such a big deal out of it?? Much like a computer without a "SAVE" button, the "experience" of OP or Stim is just not saved. So every time you experience OP or Stim would be exactly like the last time? the last brain configuration so to speak!

If that was the case, you could then potentially design opioids and/or stimulants devoid of reinforcing effect ie selective mu agonist+MGluR5 antagonist? like a non-reinforcing fentanyl?? but then again, Would there even be "euphoria" if the experience can't be remembered by virtue of blocking type 5 Glutamate metabotropic receptors in the Nucleus accumbens??...

Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats

Aim:

Glutamatergic neurotransmission in the nucleus accumbens (NAc) is crucial for the relapse to heroin seeking. The aim of this study was to determine whether mGluR5 in the NAc core or shell involved in heroin seeking behavior in rats.


Methods:

Male SD rats were self-administered heroin under a fixed-ratio 1 (FR1) reinforcement schedule for 14 d, and subsequently withdrawn for 2 weeks. The selective mGluR5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 5, 15 and 50 nmol per side) was then microinjected into the NAc core or shell 10 min before a heroin-seeking test induced by context, cues or heroin priming.

Results:

Microinjection of MPEP into the NAc shell dose-dependently decreased the heroin seeking induced by context, cues or heroin priming. In contrast, microinjection of MPEP into the NAc core did not alter the heroin seeking induced by cues or heroin priming. In addition, microinjection with MPEP (15 nmol per side) in the NAc shell reversed both the percentage of open arms entries (OE%) and the percentage of time spent in open arms (OT%) after heroin withdrawal. Microinjection of MPEP (50 nmol per side) in the striatum as a control location did not affect the heroin seeking behavior. Microinjection of MPEP in the 3 locations did not change the locomotion activities.


Conclusion:

Blockade of mGluR5 in NAc shell in rats specifically suppresses the relapse to heroin-seeking and anxiety-like behavior, suggesting that mGluR5 antagonists may be a potential candidate for the therapy of heroin addiction.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261128/

With stimulants:

A Novel mGluR5 Antagonist, MFZ 10-7, Inhibits Cocaine-Taking and Cocaine-Seeking Behavior in Rats
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942387/

 

[aced126]

Metabotropic Glutamate Receptors type 5 (mGluR5)-null mice do not show any reinforcing effects with neither opioids (heroine) or psychostimulants(methamphetamine, cocaine). In other words, mGluR5-null phenotype do not exhibit opioid or cocaine induced conditional place preference. Correct me if I am wrong!!

My question is: do opioids and psychostimulants also produce "euphoria" and other NAcc mediated effects of OPs/STIMS in mGluR5-null mice without the reinforcing present in the wild-type mice? If that would be the case, then would addition of a mGluR5 antagonist to an opiate or a stim provide both potentiation of Nacc-mediated "reward" effect of OP and Stims without the reinforcing??

MGluR5, iirc is also involved in memory consolidation, learning and perception. So the question is: does mGluR5 antagonism prevent the consolidation ot the "memory of the experience" of euphoria associated with Nacc DAergic activation? So the brain can still have good time but don't make such a big deal out of it?? Much like a computer without a "SAVE" button, the "experience" of OP or Stim is just not saved. So every time you experience OP or Stim would be exactly like the last time? the last brain configuration so to speak!

If that was the case, you could then potentially design opioids and/or stimulants devoid of reinforcing effect ie selective mu agonist+MGluR5 antagonist? like a non-reinforcing fentanyl?? but then again, Would there even be "euphoria" if the experience can't be remembered by virtue of blocking type 5 Glutamate metabotropic receptors in the Nucleus accumbens??...


With stimulants:

This is a very interesting question. I have a few thoughts. Initially I thought that by blocking the reinforcing effects, you would block the euphoria as they go hand in hand (that is to say, the euphoria mediates the reinforcing behaviour). It makes sense from an evolutionary perspective. The whole point of "feeling good" itself is in order to repeat the behaviour (which probably promotes survival in general).

However then I had second thoughts. Molecularly, it is not necessary (but I still have a sense it is the case) that the molecular mechanisms that cause "euphoria" also directly cause reinforcing behaviour. It might be that "euphoria" is caused, and then as a result of the biochemical changes that take place with euphoria, further downstream changes occur that mediate reinforcement (LTP in hippocampus etc). Reinforcement, I think, is thoroughly interlinked with memory. So it might be that mGlu5 antagonists prevent memory formation of euphoric experiences.

But then of course there is the question of why we take drugs in the first place. If we could not form memories to remember our experiences, we would not take the drug itself, and hence, we would not be here discussing this.

I think if something like this is ever used clinically, and it is able to stop reinforcing behaviours of very addictive drugs, then I have my doubts of what effects it will have on normal daily experiences. I think this could be slightly similar to lesioning parts of the brain involved in addiction and reinforcement. It's dangerous territory.

However if the issues I have put forward can somehow be averted, I can see possible uses for this. For example, it can be used to nullify the addictive and reinforcing properties of opioids, while still retaining their analgesic activity.

 

[Nagelfar]

Started WP article on MFZ 10-7 due to this, anyone welcome to fill it out with the material DotChem gave above. (In full below. why not)

 

[serotonin2A]

This is a very interesting question. I have a few thoughts. Initially I thought that by blocking the reinforcing effects, you would block the euphoria as they go hand in hand (that is to say, the euphoria mediates the reinforcing behaviour). It makes sense from an evolutionary perspective. The whole point of "feeling good" itself is in order to repeat the behaviour (which probably promotes survival in general).

However then I had second thoughts. Molecularly, it is not necessary (but I still have a sense it is the case) that the molecular mechanisms that cause "euphoria" also directly cause reinforcing behaviour. It might be that "euphoria" is caused, and then as a result of the biochemical changes that take place with euphoria, further downstream changes occur that mediate reinforcement (LTP in hippocampus etc). Reinforcement, I think, is thoroughly interlinked with memory. So it might be that mGlu5 antagonists prevent memory formation of euphoric experiences.

But then of course there is the question of why we take drugs in the first place. If we could not form memories to remember our experiences, we would not take the drug itself, and hence, we would not be here discussing this.

I think if something like this is ever used clinically, and it is able to stop reinforcing behaviours of very addictive drugs, then I have my doubts of what effects it will have on normal daily experiences. I think this could be slightly similar to lesioning parts of the brain involved in addiction and reinforcement. It's dangerous territory.

However if the issues I have put forward can somehow be averted, I can see possible uses for this. For example, it can be used to nullify the addictive and reinforcing properties of opioids, while still retaining their analgesic activity.

I think it is a mistake to think of euphoria and reinforcement this way. The neurochemical effects that lead to euphoria are sort of like tofu and are context-dependent; they are probably not inherenty pleasureable unless combined with reinforcement. Think about being on a roller coaster: the rush is fun; exactly the same feeling is horrible if you are falling to your death.

 

[DotChem]

However then I had second thoughts. Molecularly, it is not necessary (but I still have a sense it is the case) that the molecular mechanisms that cause "euphoria" also directly cause reinforcing behaviour. It might be that "euphoria" is caused, and then as a result of the biochemical changes that take place with euphoria, further downstream changes occur that mediate reinforcement (LTP in hippocampus etc). Reinforcement, I think, is thoroughly interlinked with memory. So it might be that mGlu5 antagonists prevent memory formation of euphoric experiences.

Chemically, mGluR5 antagonism does not prevent the release and/or inhibition of Dopamine reuptake by DRA/DRIs like cocaine or by opiates. So in principle, one would expect the neurochemical effect of DA release to be present regardless of mGluR5 blockade. At least physiologically. The subjective "euphoric" experience (eg of meth-induced DA release), I don't know? It hard to tell since mice and lab rats won't tell that.

But in the short term, that is following drug administration and during the period of Nacc activation, all the drug(stim/OP) induced effects such as locomotion seem to be present regardless of mGluR5 state. Removal of the blockade of mGluR5 receptors reestablish base line at least in sex behavior of male rats (cf here).

I think this could be slightly similar to lesioning parts of the brain involved in addiction and reinforcement. It's dangerous territory.

Not really!.. no more dangerous than the sleep state where we basically barely remember anything around us and wake the next morning and start again remembering our conscious experiences of the environment around us!
Amnesia induced by mGluR5 antagonism does not seem to be irrerversile (like a permanent lesion). I am not sure about the memory status (long term and short) of GluR5-/- null-mice. They seem to strive. for example, they have normal feeding behavior ie remember food (especially the one humans call cheese ). And they get pretty excited on coke or Meth! They just don't give a hoot about doing the drug again. My guess is mGluR5 is probably not involved in short term memory formation. But only in long term potentiation (I'll have to do some more reading on that).

Pretty fascinating research going on, I might add: would be interesting to see the effect the effect in humans of mGluR5 antagonists in combination with OP or Stims..etc. Some of the selective antagonists have antidepressant and anxiolytic effect in earlier clinical trials in healthy humans. Not sure why development was discontinued (may be $money$ went to other priority projects)

PS: Now, you don't want miss this review ..coming on print July 1 but have a "Delayed Embargo" . Probably goodies the SeeEyeAaa doesnt want people to see. Seriously though, DO NOT MISS IT.. lots of goodies for anybody interested in drug design targeting psychotropic effects and Nacc and related brain areas chemistry..

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate HomeostasisM. D. Scofield, J. A. Heinsbroek, C. D. Gipson, Y. M. Kupchik, S. Spencer, A. C. W. Smith, D. Roberts-Wolfe, P. W. Kalivas
Pharmacol Rev. 2016 July; 68(3): 816–871. Published online 2016 July. doi: 10.1124/pr.116.012484

Does anybody know how to access the paper. It said "Embargo till July1, 2016". here's the link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931870/

 

[DotChem]

Started WP article on MFZ 10-7 due to this, anyone welcome to fill it out with the material DotChem gave above. (In full below. why not)

@Nagelfar: here is review article on that subject, ~ 50 pages Tons of references for the WP you started.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931870/

 

[Nagelfar]

I think it is a mistake to think of euphoria and reinforcement this way. The neurochemical effects that lead to euphoria are sort of like tofu and are context-dependent; they are probably not inherenty pleasureable unless combined with reinforcement. Think about being on a roller coaster: the rush is fun; exactly the same feeling is horrible if you are falling to your death.

I once heard that statistically >90% of those who jumped from the golden gate bridge as suicides were successful, of the ~10% that survived 100% of those admitted that as they were falling, they suddenly felt a renewed zest for life and the last thought that went through their mind before they hit the water was that they didn't want to die. The two possible conclusions being that, the free falling caused a surge of dopamine that improved mood (so maybe not completely a "horrible" feeling) or that, by divine intervention, it just so happened that the select number of exactly those that changed their mind were saved from death. However, the dopamine hypothesis in this case resonates a bit with it not being an entirely horrible experience (even for the ones who died).

@Nagelfar: here is review article on that subject, ~ 50 pages Tons of references for the WP you started.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4931870/

Even articles are time release now?

 

[serotonin2A]

I once heard that statistically >90% of those who jumped from the golden gate bridge as suicides were successful, of the ~10% that survived 100% of those admitted that as they were falling, they suddenly felt a renewed zest for life and the last thought that went through their mind before they hit the water was that they didn't want to die. The two possible conclusions being that, the free falling caused a surge of dopamine that improved mood (so maybe not completely a "horrible" feeling) or that, by divine intervention, it just so happened that the select number of exactly those that changed their mind were saved from death. However, the dopamine hypothesis in this case resonates a bit with it not being an entirely horrible experience (even for the ones who died).

Here again I think you are making a mistake by equating all pleasurable feelings with dopamine.

People often have life changing experiences when facing death. They are also liable to be experiencing huge increases in the release of a variety of neurochemicals, including glutamate and endocannabinoids.

So I don't think there is any reason to attribute the effects of falling to DA.

Think about the difference between amfonelic acid and amphetamine. Amfonelic acid is reinforcing but doesn't produce a huge amount of subjective euphoria. On the other hand, amphetamine is reinforcing and many people find it to be very euphoric. Studies have reported that amphetamine-induced euphoria can be blocked by NET inhibitors, which indicates that NE likely plays a role in the euphoric effects of amphetamine.

Those findings obviously contrast with the fact that it is not particularily fun to selectively increase NE concentrations. So in general, euphoria is probably more than just DA alone and is definitely more than just NE alone.

Another example of this line of thinking is nicotine, which is obviously reinforcing via DA but is not very euphoric.

 

[Cotcha Yankinov]

I think it is a mistake to think of euphoria and reinforcement this way. The neurochemical effects that lead to euphoria are sort of like tofu and are context-dependent; they are probably not inherenty pleasureable unless combined with reinforcement. Think about being on a roller coaster: the rush is fun; exactly the same feeling is horrible if you are falling to your death.

Is what you're saying about context essentially implying that the neurons that can (under the right conditions) produce the sensation of euphoria must be co-activated/receive appropriate input from other "context" neurons? (Or the various context neurons can be responsible for inputting that the context is a dangerous situation and euphoria/trust is not an appropriate response)

I think orgasm might be a good example here? Mood and being turned on have everything to do with the ability to orgasm and enjoy the experience. A shotgun approach like a drug (even selective binding to one receptor) just may not be able to actually replicate the "context" activity necessary to produce solely horny-ness (I mean yes methamphetamine might make you horny but it comes with a host of other effects as well). Oxytocin might be something of a artificial context inducer?? I have never tried it.

So essentially what I'm getting at is, maybe the right drugs could produce specific artificial context? Maybe solely DA or solely NE messes up "context neurons" too much?

 

[MeDieViL]

Dopamine does not cause euphoria at all guys, it purely causes wanting and causes the addictive effects of drugs, the mu opioid receptor is responsible for the euphoria of all drugs, endorphine release.

The memory of a drug has barely anything to do with addiction,drugs immediatly induce changes in the brain, and are programmed as a essential need like food, in contrast to food, sex or whatever theres a lack of cellular mechanism that stops the craving after "satisfaction" like when you are full.

Glutamate is a main player in drug indued addiction, ive indentified alot of differened targets implicated in addiction, nmda, mglur, nicotinic receptor, d2, 5ht3, as an example d2 antagonism toheter with 5ht3 antagomism can reverse sensitization, i forgot in what context tough
i forgot alot of differened pathways but everytime i tought of one, looking it up with iboaine showed it acted on that pathway, oh yeah cck another one.

People with shizophrenia or that relate to it are immume to the rewarding effects of opiates, i suffer from only negatives, adhd, anhedonia, ocd, social anxiety and amphetamine wipes them mostly away, indeed it works for negatives in shizo very effectively. and indeed im immume to opiates most of the time, also they dont respond to benzos due to a defiency in nmda and glutamate which release gaba, amphetamine releases gaba trough that pathway and benzos work for any positive symptions induced by amphetamine.

i dont get any rewarding effects from alcohol, weed, opiates, benzos or dissociates without amphetamine, only after taking a sero releaser like mdma, ketamine was rewarding and as were psychedelics, opiates seemed to work after tramadol withdrawal, eg codeine, that went away and a few weeks i experienced methadone to kinda work after withdrawal but that dose was too minimal to draw any conclusions.
Cannabinoids only induce reward if codeine works added to stimulants.

What studys report that noradrenaline reuptake inhibitors block amp euphoria? thats not the case anecdotally.

Risperdal completely blocked the euphoria of amp in the past for me, but the addiction of nac, turmeric and phenibut completely reactvated the euphoric effects.

I had a potent opiate like experience on methadone when i took it with dxm, like a colorfull sleep and all good stuff as it directly acts on the reward pathway, i took it with dxm and when i think about it i feel kinda disgusted about the experience, like thinkin about sex when turned off.

 

[serotonin2A]

Dopamine does not cause euphoria at all guys, it purely causes wanting and causes the addictive effects of drugs, the mu opioid receptor is responsible for the euphoria of all drugs, endorphine release.

It is definitely true that mu opioid receptor (MOR) activation contributes to the euphoria produced by multiple drug classes. However, it would be a mistake to think that MOR is solely responsible for euphoria. If the latter claim is true then patients maintained on naltrexone or buprenorphine would not experience any euphoria from any drug, but that is clearly not the case. Additionally, in the studies that found that euphoria is attenuated by MOR blockade, the euphoric effects are reduced but are not completely eliminated, suggesting that mechanisms other than MOR activation contribute to euphoria.

For example, note that 50 mg p.o. naltrexone (a dose that completely blocks the response to hydromorphone: http://www.ncbi.nlm.nih.gov/pubmed/10463317) only reduced ratings of a cocaine-induced "high" by ~50%:
http://www.ncbi.nlm.nih.gov/pubmed/12957222

In volunteers with a history of cocaine and heroin abuse, naltrexone maintenance blocked the subjective and euphoric effects of hydromorphine but not cocaine:
http://www.ncbi.nlm.nih.gov/pubmed/8930154

naltrexone attenuates the subjective effects of amphetamine:
http://www.ncbi.nlm.nih.gov/pubmed/15538132
http://www.ncbi.nlm.nih.gov/pubmed/17957221

naltrexone attenuates alcohol-induced euphoria:
http://www.ncbi.nlm.nih.gov/pubmed/7694913
http://www.ncbi.nlm.nih.gov/pubmed/10731623

naltrexone attenuates nicotine-induced euphoria:
http://www.ncbi.nlm.nih.gov/pubmed/17696684

The memory of a drug has barely anything to do with addiction,drugs immediatly induce changes in the brain, and are programmed as a essential need like food, in contrast to food, sex or whatever theres a lack of cellular mechanism that stops the craving after "satisfaction" like when you are full.

I'm surprised that you would think that memory has little to do with drug addiction. There is actually a lot of evidence that memories of "context" play important roles in drug abuse. As an example, cocaine addicts experience craving in environments associated with cocaine because the environmental cues trigger dopamine release (signaling that cocaine use is expected to occur in the near future). However, that process requires the existance of memories linking the specific environmental cues to cocaine.

Furthermore, you have almost certainly heard of behavioral tolerance -- the phenomenon where e.g. heroin addicts have a higher tolerance to heroin in environments associated with heroin use. Obviously memories of drug use play an important role in that process.

People with shizophrenia or that relate to it are immume to the rewarding effects of opiates, i suffer from only negatives, adhd, anhedonia, ocd, social anxiety and amphetamine wipes them mostly away, indeed it works for negatives in shizo very effectively. and indeed im immume to opiates most of the time, also they dont respond to benzos due to a defiency in nmda and glutamate which release gaba, amphetamine releases gaba trough that pathway and benzos work for any positive symptions induced by amphetamine.

i dont get any rewarding effects from alcohol, weed, opiates, benzos or dissociates without amphetamine, only after taking a sero releaser like mdma, ketamine was rewarding and as were psychedelics, opiates seemed to work after tramadol withdrawal, eg codeine, that went away and a few weeks i experienced methadone to kinda work after withdrawal but that dose was too minimal to draw any conclusions.
Cannabinoids only induce reward if codeine works added to stimulants.

I would be careful when extrapolating your experiences to others individuals. Most schizophrenia patients respond to opiates, amphetamines, benzodiazepines, etc. It just isn't true to argue that your experience is universal. This issue is also complicated by the fact that many schizophrenia patients show evidence of reward deficits, as well as the fact that antipsychotics may reduce the responsiveness to some abused substances.

What studys report that noradrenaline reuptake inhibitors block amp euphoria? thats not the case anecdotally.

Atomoxetine markedly reduces subjective ratings of the amphetamine-induced "high":
http://www.ncbi.nlm.nih.gov/pubmed/20014909

High doses of the DA D2/3/4 receptor antagonist pimozide does not attenuate amphetamine-induced euphoria:
http://www.ncbi.nlm.nih.gov/pubmed/9050084

It is not surprising to me that you wouldn't notice an interaction between atomoxetine and amphetamine. Detecting interactions between uptake inhibitors and releasers is very dose dependent. If you are not using a high enough dose of the uptake inhibitor then it might only produce a slight reduction of the drug effect.

 

[MeDieViL]

It is definitely true that mu opioid receptor (MOR) activation contributes to the euphoria produced by multiple drug classes. However, it would be a mistake to think that MOR is solely responsible for euphoria. If the latter claim is true then patients maintained on naltrexone or buprenorphine would not experience any euphoria from any drug, but that is clearly not the case. Additionally, in the studies that found that euphoria is attenuated by MOR blockade, the euphoric effects are reduced but are not completely eliminated, suggesting that mechanisms other than MOR activation contribute to euphoria.

For example, note that 50 mg p.o. naltrexone (a dose that completely blocks the response to hydromorphone: http://www.ncbi.nlm.nih.gov/pubmed/10463317) only reduced ratings of a cocaine-induced "high" by ~50%:
http://www.ncbi.nlm.nih.gov/pubmed/12957222

In volunteers with a history of cocaine and heroin abuse, naltrexone maintenance blocked the subjective and euphoric effects of hydromorphine but not cocaine:
http://www.ncbi.nlm.nih.gov/pubmed/8930154

naltrexone attenuates the subjective effects of amphetamine:
http://www.ncbi.nlm.nih.gov/pubmed/15538132
http://www.ncbi.nlm.nih.gov/pubmed/17957221

naltrexone attenuates alcohol-induced euphoria:
http://www.ncbi.nlm.nih.gov/pubmed/7694913
http://www.ncbi.nlm.nih.gov/pubmed/10731623

naltrexone attenuates nicotine-induced euphoria:
http://www.ncbi.nlm.nih.gov/pubmed/17696684



I'm surprised that you would think that memory has little to do with drug addiction. There is actually a lot of evidence that memories of "context" play important roles in drug abuse. As an example, cocaine addicts experience craving in environments associated with cocaine because the environmental cues trigger dopamine release (signaling that cocaine use is expected to occur in the near future). However, that process requires the existance of memories linking the specific environmental cues to cocaine.

Furthermore, you have almost certainly heard of behavioral tolerance -- the phenomenon where e.g. heroin addicts have a higher tolerance to heroin in environments associated with heroin use. Obviously memories of drug use play an important role in that process.



I would be careful when extrapolating your experiences to others individuals. Most schizophrenia patients respond to opiates, amphetamines, benzodiazepines, etc. It just isn't true to argue that your experience is universal. This issue is also complicated by the fact that many schizophrenia patients show evidence of reward deficits, as well as the fact that antipsychotics may reduce the responsiveness to some abused substances.



Atomoxetine markedly reduces subjective ratings of the amphetamine-induced "high":
http://www.ncbi.nlm.nih.gov/pubmed/20014909

High doses of the DA D2/3/4 receptor antagonist pimozide does not attenuate amphetamine-induced euphoria:
http://www.ncbi.nlm.nih.gov/pubmed/9050084

It is not surprising to me that you wouldn't notice an interaction between atomoxetine and amphetamine. Detecting interactions between uptake inhibitors and releasers is very dose dependent. If you are not using a high enough dose of the uptake inhibitor then it might only produce a slight reduction of the drug effect.

I never make any conclusions solelyyy based on my own experience, altough its contributing to any conclusion i may make, i concluded that many patients with shizophrenia are immume to benzos and or opiates based on a ammount of anecdotes. please post links to anecdotes which makes you conclude the majority does respond to benzos and opiates.

The reward related issues dont complicate anything, as imo it does see to indicate a connection to the anhedonia, also i based this on anecdotes of ppl that dont take aps, olanzapine as an example makes codeine work for me, so perhaps your conclusion is based on individuals where the brain is more normalised by aps, they reverse alot of abnormalities in shizo patients.

I also remember bein able to feel., well that insanely strong russian benzo on risperdal a bit while i normally never noticed it at all.

Sure atomexetine reduces the euphoria or amp a bit, this doesnt mean a thing as its only a reduction of euphoria, which can be explained by the crucial role of ne of the brain to be able to facilate anhedonia and atomexine is far from selective as it also acts on the kappa receptor as an example.

indeed doses play a role, but i havent seen any evidence that the ne release mediates the euphoria, the da antibiotic was euphoric for me and it doesnt modulate ne, also shows that da release does not directly corrolate with euphoria, 3fa and desoxy are ore dopamineric then amp but induce alot less euphoria.

dont know what your trying to show with that pimozide study, alot of potent aps dont block amp euphoria at all, adding to the evidence showing that da isnt the cause of the euphoria.

As for environment related cues, alot of things make you think of natural rewards like food or sex, everyone gets this, only a fraction suffers from food or sex addiction.

when addiction is there its obvious a cue can induce relapse,, this simply shows that its like throwing a brick on a dying man, while the healthy guys just simply duck out of the way.

that heroin example also doesnt show more then a modulatory role on a existing problem, food in a restaurant tastes niccer then at home perhaps, this doesnt neceserry corrolates to the root causes of addiction at all.

the mu opioid receptor is extremely complex, opioid tolerance can occur by a diff mechanism then just receptor downregulation, also its well established that mu plays a major role in mood and pain, if naltrexone is evidence that mu perhaps isnt the main player in euphoria, then we also have to assume that naltrexone proofs that the proposed role of mu in pain, mood etc

Mu activation can stop producing the same effects by adaptive changes by downstream pathways such as nmda even tough the receptor is as sensitive, naltrexone also blocks kappa which kinda abolishes the negatives of mu blockade in a way, the functionality of mu is extremely complex.

There is tons of evidence pointing to the involvement of mu in likin, while there is no evidence for das involvement if you rule out wanting causing effects simular to liking in rodents.

you may be right that mu isnt the main player, you did post some evidence pointing to that, but theres no evidnce at all conclusively pointing to dopamine, as wanting explains the evidence that looked like it pointed to that.

 

[MeDieViL]

Suicide is of evolutionary purpose as telling ppl you want to kill yourself makes them shoot into action to try and provide help, thats why most individuals allways tell other instead of actually killing themselves, its not suprising that ppl would regret jumping of that bridge as the suicide response seems to be of evolutionary advantage and is more like an illusion, maybe jumping makes the brain think you did soething caused by feeling suicidel so youd get help?

 

[Cotcha Yankinov]

Aren't the MOR's (that contribute to euphoria) mainly inhibiting inhibitory interneurons, therefore pre-synaptic neurotransmitter release with for example serotonin could bind to an inhibitory serotonin receptor (or whatever is expressed post synaptically) and thus serotonin could function similar to a MOR agonist? (Albeit much much weaker).

I suppose I'm personally not as interested in the neurotransmitters etc. that have been found to mediate euphoria but I'm rather more interested in the specific brain cells that are closest to causing euphoria.

 

[serotonin2A]

I never make any conclusions solelyyy based on my own experience, altough its contributing to any conclusion i may make, i concluded that many patients with shizophrenia are immume to benzos and or opiates based on a ammount of anecdotes. please post links to anecdotes which makes you conclude the majority does respond to benzos and opiates.

Why would we want to base a discussion of pharmacology on anecdotes? I'm sure you recognize that anecdotal evidence is often wrong. It should be clear that schizophrenia patients are not immune to benzodiazepines because agents from that pharmacological class are often used to sedate schizophrenia patients. Likewise, if schizophrenia patients are immune to opioids, then how is it possible for schizophrenia patients to become addicted to opioids? Morphine was a popular treatment for schizophrenia prior to the discovery of antipsychotics, which wouldn't make any sense if schizophrenia patients are immune to the effects of morphine.

Use of benzodiazepines in schizophrenia patients:
http://www.ncbi.nlm.nih.gov/pubmed/1674645
http://pb.rcpsych.org/content/24/3/113

opioid addiction in schizophrenia patients:
http://www.ncbi.nlm.nih.gov/pubmed/25392062
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905490/

some schizophrenia patients use morphine as an antipsychotic:
http://www.ncbi.nlm.nih.gov/pubmed/6961866

The reward related issues dont complicate anything,

My point was that the disruption of reward in schizophrenia patients complicates assessment of their subjective responses to abused drugs. If some patients exhibit a blunted reward response to particular drugs, then that could give them the impression that they are immune to the effects of the drugs. Their impression would be wrong -- they are not actually immune to the overal psychopharmacologic response to the drugs -- but it would explain why some patients may believe they are immune.

Another factor that may contribute is the fact that some schizophrenia patients have an affective state that is far from normal baseline. So instead of sedating schizophrenia patients, opioids and benzodiazepines would tend to shift their affective state into the normal range. But that doesn't mean that the patients are immune to those drug classes; the patients actually just have a shifted baseline.

Sure atomexetine reduces the euphoria or amp a bit, this doesnt mean a thing as its only a reduction of euphoria, which can be explained by the crucial role of ne of the brain to be able to facilate anhedonia and atomexine is far from selective as it also acts on the kappa receptor as an example.

I don't get your rationale for dismissing this study. Antagonist blockade experiments are a fundamental tool of psychopharmacology. If an antagonist blocks a drug effect, then that serves as evidence that the site is involved in the mechanism of action. No drug is completely selective for a single target, so it is not surprising that atomoxetine has off-target effects. But none of the other known targets of atomoxetine makes sense in the context of the atomoxetine-amphetamine interaction. Kappa activation is associated with dysphoria, not euphoria, so it doesn't make sense that the euphoric effects of amphetamine would be mediated by kappa receptors.

the da antibiotic was euphoric for me and it doesnt modulate ne,

Controlled studies, as well as anecdotal reports of other users, have shown that amfonelic acid is reinforcing but not very euphoric. Your observation reveals one of the problems with anecdotal claims -- I'm guessing you have no way of knowing if what you ingested was pure amfonelic acid? RC suppliers sometimes sell mixtures of drugs as pure compounds. I'll stick with the reports from actual studies and from psychopharmacologists who verified the identity of their samples.

dont know what your trying to show with that pimozide study, alot of potent aps dont block amp euphoria at all, adding to the evidence showing that da isnt the cause of the euphoria.

The point was that if DA is responsibe for amphetamine-induced euphoria then pimozide should be able to block the effect. It is another important piece of evidence that DA is not the exclusive mediator of the euphoric effects of amphetamine.

As for environment related cues, alot of things make you think of natural rewards like food or sex, everyone gets this, only a fraction suffers from food or sex addiction.

when addiction is there its obvious a cue can induce relapse,, this simply shows that its like throwing a brick on a dying man, while the healthy guys just simply duck out of the way.

that heroin example also doesnt show more then a modulatory role on a existing problem, food in a restaurant tastes niccer then at home perhaps, this doesnt neceserry corrolates to the root causes of addiction at all.

You are making a bunch of random statements here that don't actually address my point: People crave cocaine because the dopaminergic system is conditioned to increase dopamine release in response to environemental cues that are associated with cocaine use. For that process to occur, the brain has to learn and recall that cocaine has been used in a articular environment. How would it be possible for the brain to learn those associations if memories have not been formed?

the mu opioid receptor is extremely complex, opioid tolerance can occur by a diff mechanism then just receptor downregulation, also its well established that mu plays a major role in mood and pain, if naltrexone is evidence that mu perhaps isnt the main player in euphoria, then we also have to assume that naltrexone proofs that the proposed role of mu in pain, mood etc

You are making this way too complicated. Naltrexone blocks MOR receptor activation, so if an effect is mediated by MOR activation then naltrexone will block it. We're talking about acute administration, meaning that tolerance and desensitization are irrevelant. The papers made it through peer review, so the underlying pharmacology is likely sound.

Mu activation can stop producing the same effects by adaptive changes by downstream pathways such as nmda even tough the receptor is as sensitive, naltrexone also blocks kappa which kinda abolishes the negatives of mu blockade in a way, the functionality of mu is extremely complex..

Again, none of that would explain why naltrexone would fail to block an acute effect mediated by MOR.

you may be right that mu isnt the main player, you did post some evidence pointing to that, but theres no evidnce at all conclusively pointing to dopamine, as wanting explains the evidence that looked like it pointed to that.

I agree that DA isn't the prime mover of euphoria. And I also agree that MOR contributes in certain situations. Although it is nice to be able to tie up an explaination into a neat package ("MOR mediates euphoria"), the pharmacology is not so black and white, and I was pointing that out.

 

[MeDieViL]

If opiates or benzos shift their mental state then they are clearly not immume, also this is based on acedotes where ppl dont respond to any dose at all, a blunted responseponse or a shift to normality is obviously not imunity,im talking about ppl that only respond to opiates when combining them with stimulants or ppl suddenly becoming immume during the predromal stage, i dont think anyone would mistake a blunted response or a shift to normality with being immume, like taking oxycodone doses that would normally kill a opiate naive individual as they dont get any effect on heartrate of breading either.
i shouldnt have generalised tough, there are differened subtypes of shizo and this is mostly relevant to a subtype of shizoes that are of the mostlynegative symption type,imnot suprised actually it can wotk for positive symptions.

paradoxal responses are the standard in shizo,again i shouldnt have generalised.

Strattera modulates kappa in a special again, but you didnt respond tome, it blunts the euphoria a bit, how is that evidence that ne plays a crucial role? you said ne reuptake inhibitors block the euphoria and i havent seen any effects of that

strattera activates kappa
kappa causes dysphoria
its a weak modulator so blunting the euphoria a bit makes sense

there are several anecdotes of reboxetine dramatically potentiating the energy of amp without blunting the euphoria.

Yes naltrexone blocks,so if an effect is medicated by mor naltrexone should block that, if thats the cause then the accepted normal functions of themu opioid receptor would be completely wrong, its accept themu receptor regulates mood,pain etcnaltrexone doesnt induce those issue, and kappa doesnt induce this issues ust as strong as mu would reduce them,atleast theres no evidence of that if you want to claim kappa fully negates any negatives.

Memorys play a role in addiction,eg the big cue, but without but i have yet to see evidence this is the cause of addiction, recreational drug users have the samething, its just something that aggrevates addiction when its induced in the brain, offcourse those associations are crucial in a way to want to drug, but that often goes in arecreational way or ppl have the same assocition after using a drug just once and never again, im just stating its not a key mediated in the addiction problem,which at its root cause is caused by differened issues.

eg i havent seen evidence that ibogaine removes thosememorys, yet in alot of ppl it completely reverses addiction.

But anyway you provided evidence enough forme to change my conclusion that mor is the main player, it does look like that however again naltrexone doesnt completely abolish the effects of mu opiod receptor in the brain, atleast what we all scientifically agree with as naltrexone doesnt induce any unpleasant effects, which means either that what we thinkmor does is wrong or that modulation of other receptors somehow bypasses mu to induce simular downstream pathways and effects, because as you know its not the receptor doing anything, its merely a button that causes effects by the downstream effects of pressing that button.

Risperdal completely abolished amphetamine euphoria for me, maybe because the strong da blockade maybe blocked the endorphin release or whatever,but adding turmeric,nac and phenibut, which act on reward related pathways, creb, mglur2 and 3 and gabab,and suddenly the euphoric effects of amp where back fully there.

Need to find where i red this,but d1 antagonism reduces the euphoria of heroin, but chronic blockade increases the euphoria.

Please wait with replyin i need to add some stuff

 

[serotonin2A]

You are certainly welcome to collect your thoughts and edit your post. I'll wait to reply. But I did want to respond to your claim that atomoxetine is a kappa (KOR) agonist. There isn't any evidence that atomoxetine produces effects that are mediated by KOR in vivo, and there are several good reasons to think that it is unlikley to have such effects.

Atomoxetine itself has low affinity for KOR (it has almost 1000-fold higher affinity for NET vs. KOR). However, the metabolite 4-hydroxyatomoxetine does have relatively high affinity for KOR (Ki = 95 nM) and reportedly acts as a partial agonist. Just going by those numbers, however, doesn't show that atomoxetine is likely to activate KOR in humans because the pharmacokinetics of atomoxetine must be taken into account. In patients treated with atomoxetine, blood levels of 4-hydroxyatomoxetine ranged from undetectable to ~1 to 3% of the atomoxetine concentration (http://dmd.aspetjournals.org/content/31/1/98.long). The reason why there is so little 4-hydroxyatomoxetine in patients is that it is rapidly metabolized to an inactive gluconuride metabolite). What that means is that there is almost no chance that someone taking atomoxetine would have high enough blood levels of 4-hydroxyatomoxetine to activate KOR in the CNS.

It must also be considered that 4-hydroxyatomoxetine is also a NET inhibitor (Ki for blocking NET uptake in rat hypothalamic synaptosomes is 3 nM). The fact that 4-hydroxyatomoxetine is about 30-fold selective for NET inhibition vs. KOR binding makes it highly unlikely that patients are taking atomoxetine at doses that would impact KOR. For atomoxetine use to result in appreciable levels of KOR activation, patients would have to be taking doses that produce far greater than 100% blockade of NET.

Don't forget that 4-hydroxyatomoxetine is a partial KOR agonist, meaning low levels of occupation would produce very little KOR activation.

But most importantly, atomoxetine doesn't produce subjective effects similar to those of other KOR agonists, like dysphoria and hallucinations. Such effects would be very obvious.