The workings of amphetamines, work and reward

Solipsis

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Can anyone give some advanced insight into how the action of amphetamines relates to productivity, reward 'arcs' and satisfaction?

Because some parts of this always kind of surprise me or feel counterintuitive. A lot of people associate dopamine with reward, but from what I understand the reward system is deeply connected to doing tasks/work that we expect a reward from creating a sort of tension arc?

So how can it be explained that amphetamines can increase irritability / feeling pissed off? Is this a kind of frustration related to dissatisfaction of expecting to have more work done but not feeling like enough is getting done - a sort of impatience and warping of this reward arc?

I don't really understand this, shouldn't amphetamines help with adding both productivity / motivation to work as well as satisfaction from it? Is it a matter of expectation management where one has the experience of not getting enough done even though this doesn't necessarily have anything to do with reality: does it point to too low or too high dosage amphetamines / having too many unrealistic expectations?
 

Captain.Heroin

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I can give you a lot of insight. I’ll try to type it up for you.

This is coming from someone who is creative/productive on methamphetamine.
 

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NACC DA = reward sensation, not same as euphoria, pleasure, or really why people want to use drugs in the first place; it's more of why people want to keep using a drug blindly without necessarily getting more effects.

Increase of NE, 5HT along with DA is why MAOI antidepressants work as antidepressants, why monoamine releasers are euphoric/enjoyable/reinforcing.

Lifelong depressives / 'dementia lifelong disease', whatever, catch-all laundry list of mental disorders, tend to respond well to methamphetamine. These people tend to have creative/productive abilities of an essentially great mind that is just suffering from a disorder. The disorder keeps creativity at bay. Releasing that is like releasing a lot of pent up creativity that never got to be expressed. (Oh I know I devolved into non-chem talk...better reel 'er back in because I see I'm in NPD...ADD...I have ADHD) The only way I remembered to even respond to this post was to keep it up on my phone and I had like 10 reminders before I hopped on a desktop. JFC.

I don't find methamphetamine addictive, though highly reinforcing and very euphoric. No problems quitting it. Been years since I've shot it and don't consciously miss it though I often dream of it. Like a long-departed extremely attractive lover you hope one day will be back so you can get laid. But I will be alright without meth, kind of odd.

Almost every other person I've met succumbs to psychosis or addiction to the drug and are largely anti-intellectuals or end up that way due to the destructive force of the addiction.

Unless you're already desiring to fuck off from others and just be by yourself in an ultra-productive mode, and already known how to do this and are decent at it, it's not going to be the wonderdrug (Wunderdroge) you want.

from what I understand the reward system is deeply connected to doing tasks/work that we expect a reward from creating a sort of tension arc?
It's a system to reinforce otherwise undesirable behaviors, i.e. fucking, shooting dope, fucking and shooting dope. Doing repetitive work without reward or appreciation. Being alone for long periods of time without feeling lonely.

"expect a reward" = not what reward circuits are. It's better termed reinforcement circuits.

The "reward" is the obsessive/compulsive ritual your brain/body form together. It's not a "reward", it's a terrible curse.

how can it be explained that amphetamines can increase irritability / feeling pissed off?
You're trying to intellectualize the state of a meth-user. The average meth-user has shit for brains. Especially while on methamphetamine, even if they are geniuses off of it. It tends to incapacitate people from higher brain functioning i.e. executive functioning, responsible decision making.

The irritability can be easily parodied to my PTSD-ridden brain. Too much NE; DA vesicles get burnt up and the NE keeps going strong. Wide awake. You know you're suffering from something mentally when on day 6, 7 you're still getting phenomenal DA release and everyone else around you has burnt out, fallen apart, gotten in trouble, disappeared and ended up suffering, coming down, withdrawal, cravings for more and then when they do it it's no longer euphoric, etc.

The kind of person who can really enjoy methamphetamine is typically not the kind of person you want to know in life.
 
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AlphaMethylPhenyl

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In the vast majority of cases, antidepressants are effective until they're serotonergic.

Methamphetamine is a neurotoxin...it will make neurodegenrative diseases even worse after a short period, especially Parkinson's.

Really? But really? Meth is wildly addictive mate. Maybe you're the 1/1000 exception? I dunno, weird thing to say though, at least misleading.

Intellectualism isn't a buffer against addiction. More so, when it applies to stimulants, as intellectualizing increases the reward and utility of stimulants.

I can't make sense of what you're otherwise saying.
 

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I would say that the effects you describe probably point to too high doses, and/or too frequent dosing. I don't have too much insight into the neurochemistry and dopamine specifically as it relates to irritability, but from my laypersons understanding it's probably something to do with the interaction between dopamine and serotonin. Many dopaminergic stimulants have seronergic activity as well, and (excuse the broscience I am about to spew here) the serotonin system is notoriously a little more "fragile" than the dopamine system, more prone to damage, and takes longer to recover.

Low serotonin is often linked to irritability (complicating factors with other neurotransmitter systems obviously play a part also here but I won't go into this for simplicity, and also as I just don't have enough knowledge) so I would suspect that with sustained or higher doses the serotonin system starts to burn out, so to speak, before the dopamine system does, and this disrupted neurotransmitter balance contributes to the less desirable effects.

Other hormones probably play a part also such as cortisol, as too much stimulation is hard on the body and likely triggers the release of these "stress hormones", leading after a while to increased feelings of stress, irritability and mental fatigue which are all somewhat linked, and eventually are not counterbalanced by the overactivation of the brain's "reward" pathways.

I was thinking I read something before that suggested methylphenidate had a lower incidence of these side effects compared to amphetamine, and methylphenidate has less serotonergic activity so this would seem to be in support of my broscience hypothesis - but this might not actually be accurate so please don't take me at my word for this.

Just found this study which is somewhat interesting and related: Changes in behavior as side effects in methylphenidate treatment: review of the literature

In a study of seven healthy adult humans, a dose of 0.25 mg/kg body weight or higher resulted in the inhibition of more than 50% of dopamine transporters. Long-term treatment with methylphenidate in humans led to significantly increased activity in the caudate and putamen regions. Wang et al suggested that the increased activity of dopamine transporters compensates for their pharmacological inhibition, resulting in increased inattention and the need for an increase in the dose administered.
This study was actually inconclusive, and obviously it is not discussion an amphetamine, but the quoted section above specifically relating to long term treatment and incidence of negative side effects seems to imply that changes induced in dopamine transporters are the cause of these side effects. I initially interpreted this to mean that the increased dopamine activity is an effort to compensate for changes going on in other neurotransmitter systems which initially hold up but eventually can't keep up and the positive effects of increased dopamine start to be negated by the changes in other neurological systems... but actually maybe not, maybe this just implies that it's changes in the dopamine system alone that over time just make these substances more likely to induce undesirable effects.

Again, please excuse my prolific butchering of the science and please, someone correct me here if I'm way off. I maybe shouldn't be posting as I am on a cathinone right now and thus have a desire to research and communicate, but my judgement is probably impaired, including my judgement of the accuracy of my judgement, but this is a topic that interests me also so thought I'd give my 2c...

One final point - I believe there are recent studies suggesting that prescribed amphetamines in reasonable doses actually do not generally cause lasting maladaptive changes to reinforcement/reward pathways as it was once thought (and as some stimulants, ie, cocaine, most definitely do), so again, dosage and pattern of use is obviously important here.

Of course, as you mentioned, there is probably also a psychological aspect which is no doubt translated to a neurochemical explanation although I don't know how to do so - amphetamines speed up your thinking, so it's probably easier just to get frustrated when the world or your actions in it can't keep up - hence irritation.

Not so sure about methamphetamine. Obviously this is heavily serotonergic, but it is also prescribed in low doses very rarely and I believe there is a threshold dose where neurotoxicity is not apparent (am I correct here? Someone please tell me, as I type this I am not so sure). In my very limited experience with both amphetamine and methamphetamine I actually found the former to be MORE prone to inducing irritability on the comedown - which would support the idea that serotonin/dopamine balance is a factor - but I just don't have enough experience or knowledge again to say if this is the norm.

Hopefully someone with a solid understanding of amphetamine neuropharmacology can chime in!
 

som3dankbudz

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From what I've heard, methamphetamine is neurotoxic at even low doses; due to serotonergic qualities. Dexamphetamine on the other hand, is only neurotoxic at higher amounts, and its slightly serotonergic. Especially to those who are naive or non tolerant to it. I believe neurotoxicity is a factor via sensitization of only moderate dose dexamphetamine; not because of serotonergic qualities, because increased DA/NE levels especially being harmful to peripheral nervous system. As far as I know your correct about the sertonergic system being more fragile. As with MDMA many people question whether the sertonergic neurotoxicity is what causing their distress, if there is any, that would be on the other hand. Stimulation is a general term for what you are describing. In other circumstances reinforced purposefully inflicted GABAnergic disturbances, or what looks like them; aka amphetamine use increased MOA's in general. All I'm saying is that stimulation in other circumstances; under different MOA regulation(or misregulation as in sensitized amphetamine users) is not always agitating, irritating, anxiety, etc or "the problem". Methylphenidate if you were tolerant to amphetamine of any type would buy you some time; being a DNRI, not a Monoamine releaser. If the problem is gabanergic(what regulates the monoamines) it won't help, it won't as far as methylphenidate being a DNRI; in general more NE is inhibited in equal potent doses. AKA more agitation, and irritability; the fact that it's not as serotenergic(I believe it does have a downstream effect on serotonin, not sure though, turns out mph weakly blocks the reuptake of serotonin-nothing to worry about as far as being neurotoxic https://www.pharmgkb.org/pathway/PA166181140)is not an advantage unless your worried about neurotoxicity. What dose is your dexamp solopsis? NMDA antagonism comes to mind as regulating the reward, or what initiates the action expecting a reward. An as some what getting at above; increased DA is only desirable in certain parts of the brain I believe.(?) VTA, VTA2, Nucleus acumbens(slightly even low dose dexamp hits this; doesn't continue to above about 7.5 - 10mg.) In the peripheral nervous system increased DA is not a good thing from what I understand ex. ridgid posture, pressured speech. There is some benefit to having some modulation in these DA circuits. Then there that whole nmda antagonism inhibiting glutaminergic activity that makes these modulations in the DA system less relevant.
 
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Captain.Heroin

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Methamphetamine is a neurotoxin...it will make neurodegenrative diseases even worse after a short period, especially Parkinson's.
I think sekio and I have discussed methamphetamine's potential as a neurotoxin and it is quite low; I am sure alcohol is much, much worse.

Not all of us are aiming to end of life stages with degenerative diseases, but thank you for including this information.

Intellectualism isn't a buffer against addiction.
It literally makes addiction more frequent as addiction is a form of aberrant learning.

If you couldn't make sense of the post please read this like 10 times

Almost every other person I've met succumbs to psychosis or addiction to the drug
This is a major WARNING for the average user. When I read things like this about MDPV I chose not to use it or anything like it, as I am sure many other people chose to abstain from as well.

DA is only desirable in certain parts of the brain I believe.
This. I didn't touch on this but it is very true.
 

AlphaMethylPhenyl

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^I'm going to let the mods fix that, not going to respond.

Just for the sake of information, negative symptoms of schizophrenia are widely thought to highly correlate with lack of dopaminergic activity (D1/D5 subtypes) in the cortical region. And negative symptoms severity is ultimately most significant in prognosis, not positive symptoms (hallucinations, delusions, and so on). So, things aren't that black and white, at least not as much as you state.

I'd recommend taking a behavioral neuroscience course. They have some free online ones.
 
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Captain.Heroin

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negative symptoms of schizophrenia are widely thought to highly correlate with lack of dopaminergic activity (D1/D5 subtypes) in the cortical region. And negative symptoms severity is ultimately most significant in prognosis, not positive symptoms (hallucinations, delusions, and so on).
Oh, that's probably not true at all (the latter part). Positive symptoms are what get schizophrenics into trouble, with a charge, in jail, etc.

The first part I already knew and didn't attempt to contradict. There's structural differences inherent to us, which is why people have a huge array of potential behavioral effects from using methamphetamine.
 

Solipsis

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Hey thanks for your replies I appreciate it!

I read and am still reading.. I really should have said like in the other thread that this is about therapeutic dexamphetamine XR at rather low dosages which are effective for me.. Usually not higher than 10 mg so roughly 5 mg normal potency.

Cpt Heroin, your suggestions about reinforcement are interesting and I def know what you mean.
But recreational use of stims is just another ballgame if you ask me. Cause I think as medicine dex mostly reinforces good behaviors for me just from having more structure and basic habits and having help translating my chaotic creativity into being productive since i do have ADD.. Its a tradeoff as many will say.

Vastness thnx that does apply more to me, maybe it doesn't completely have to do with reward systems. By the way i think what i call the reward arc is basically the same as the effect of a reinforced system creating expectations of further neural stimulation.

Irritability and agitation seem to be common side effects with therapeutic amps (not even talking about aspects of amp or meth abuse).. And i think it can just as easily happen without being serotonin drained but not sure.

More later
 

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Re: the aggression/frustration feeling; this is likely due to the latter effects when the DA goes away but NE is still surging. It can cause panic attacks, physiological symptoms like not being able to stand up without feeling like one might fall over, puking nausea.

The best way to counteract this is to take a large-ish BZD dose, i.e. 4mg alprazolam (2, and then 2 an hour later if 2 doesn't do it) and you'll get in a good place again.

I imagine peripheral NE blockers on the heart would suffice in part as well.
 

som3dankbudz

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To Cap heroin:DA still being present in the synapses when these neg side effect occur

Re: the aggression/frustration feeling; this is likely due to the latter effects when the DA goes away but NE is still surging. It can cause panic attacks, physiological symptoms like not being able to stand up without feeling like one might fall over, puking nausea.

The best way to counteract this is to take a large-ish BZD dose, i.e. 4mg alprazolam (2, and then 2 an hour later if 2 doesn't do it) and you'll get in a good place again.

I imagine peripheral NE blockers on the heart would suffice in part as well.
This is not entirely true, there is often a lot of unmetabolized DA in the synapses; even when large amounts of metabolized DA have built up, or directly released NE. .It goes l-tyrosine->l-dopa->dopamine->norepinephrine->epinephrine. The initial spark of released monoamine on the reward circuits, and weakly inhibited DA/NE as with amphetamine; before desensitization/downregulation occurs. Meaning that this DA that was released and weakly inhibited is often still a factor, and just isn't rewarding you(well it is still doing so lol)due to desensitization/downregulation. Not saying that DA being metabolized into NE, on top of released, and weakly inhibited NE(and DA of course) isn't a factor. Just that often there is still lots(well moderate at least) of unmetabolized DA in the synapses when these negative symptoms appear. When these 2 monoamines are regulated by a GABAnergic or Benzo when negative symptoms of not just NE, but DA as well. DA itself causes a lot of negative symptoms once desensitization/downregulation occurs, and even before hand especially in other parts of the brain excluding the NA, VTA, VTA2. One question Solopsis, Are you sure your dosage of dexamphetamine is not higher? Or if any meth is involved.? Just because serotonergic activity is relevant to these negative side effects esp frustration. This desensitization/downregulation resulting in tolerance, while there is still a lot of DA in the synapses. Sensitization amphetamine in general proves my point. As in even at the same dosage, getting more in more sensitized to the effects of released, and somewhat inhibited DA mostly, and IMO somewhat NE. One explanation is REM sleep being the brains main way of repairing these reward circuits, and regulating desensitization and down regulation of DA circuits(also NE pathways). Maintaining homeostasis in other words. Although sensitization of the effects of DA occur while awake, and long time stress on these not just these reward pathways(like the via,vta2, NA, desensitization/downregulation occurs to the rewarding effects of amphetamine). While other parts of the brain, and other DA pathways sensitize to this DA being in the synapses?(Can't recall how this sensitization occurs?) Normally for this sensitization to occur at least somewhat acutely; there is a raise in dosage. Resulting in DA building up in the peripheral nervous system, and in other parts of the brain; even if not rewarding because there is a lack of GABA to regulate it, and even if rewarding you via the NA, VTA, VTA2. There is too much DA/NE in other pathways/parts of the brain for GABA to regulate equaling even acutely causing worsening of side effects even if the reward centers of the brain are still stimulated. Idk if you ever experienced a fake "comedown", lol, where your under the impression it has worn off and you are under the impression all that is left is peripheral stimulation, and side effects. When in reality you are still heavily/moderately under the influence. This used to happen to me when I was younger, and I was not at all trying to abuse the amphetamine what so ever. Then if benzodiazepine or alcohol is administered you realize that you are still under the influence and etc. Idk why I brought that up; just something I thought about This is what I would call now a days due to ignorance of potency, recreational doses, or accidental come ups. While getting more and more sensitized to the negative effects of DA/NE(I'm not able to recall how the brain sensitizes to DA/NE after long time amphetamine use causing worsening of side effects(well to amphetamine itself, strangely enough I am well versed on amphetamine sensitization. I suppose the stimulation to access my knowledge of such is not accessible/present.), and more "peripheral side effects" even at smaller dosage. This is after down regulation occurs, but I know what you are getting at though; clonidine is very useful for that circumstance. Being an alpha 2 Noradrenic blocker. Helps regulate excess norepinephrine. Although adding a Benzo(GABA a agonists) is often effective at making this sensitization, and in your case making side effects of the amphetamine more tolerable, or bringing back some of the rewarding effects. Use Benzo as last case scenario. I warn you, this is opening up a whole different can of worms. Please give the clonidine if available, or guanfacine brain name inutiv, another alpha 2 noradrenalic blocker. It might have another mechanism of action; I'm not sure. Or, at least, try a small dose of clonidine like 0.1mg and a smaller amount of benzos; if they are a must(if dependent, and would be taken regardless, or if being taken earlier or at higher doses due to amphetamine exasperating Benzo wd. If you are not Benzo dependent you should definitely try the clonidine. If you are; you should take the clonidine; when needed for side effects, and the Benzo at the time you normally take it. Or if it the Benzo is a must, try taking a smaller amount like 2mg alprazolam, and a 0.1 clonidine. If not of any CNS depressants. On another note; Clonidine is very dangerous with CNS depressants and should not be mixed with opioids/opiates or another CNS depressants. If you choose to mix it with CNS depressants please use extreme caution in doing so. Even if there is a stimulant on board. physiological symptoms like not being able to stand up without feeling like one might fall over <- I believe this side effect is from vaso constriction/high blood pressure, or focusing on something for long amounts of time if non tolerant or at higher doses.
 
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Seppi

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I'm writing this while half-asleep and didn't proofread so there may be nonsensical/butchered sentences or typos. Too tired to do that RN.


FWIW, dopamine in the nucleus accumbens regulates motivation in general, not just reward motivation. The NAcc is the most important brain structure in both aversion and reward systems (the former isn't really well researched, but it's very well established the the NAcc is responsible for assigning motivational salience in general and aversive salience [via D2-type NAcc MSNs] and incentive salience [via D1-type NAcc MSNs] in particular). As an aside, the NAcc contains both a hedonic hotspot and a hedonic coldspot and participates in both classical/operant conditioning (e.g., it mediates Pavlovian-instrumental transfer), so it's involved in the regulation of every key function of these systems (i.e., motivation, pleasure/displeasure, and associative learning) as well.

One final point - I believe there are recent studies suggesting that prescribed amphetamines in reasonable doses actually do not generally cause lasting maladaptive changes to reinforcement/reward pathways as it was once thought (and as some stimulants, ie, cocaine, most definitely do), so again, dosage and pattern of use is obviously important here.

Of course, as you mentioned, there is probably also a psychological aspect which is no doubt translated to a neurochemical explanation although I don't know how to do so - amphetamines speed up your thinking, so it's probably easier just to get frustrated when the world or your actions in it can't keep up - hence irritation.

Not so sure about methamphetamine. Obviously this is heavily serotonergic, but it is also prescribed in low doses very rarely and I believe there is a threshold dose where neurotoxicity is not apparent (am I correct here? Someone please tell me, as I type this I am not so sure). In my very limited experience with both amphetamine and methamphetamine I actually found the former to be MORE prone to inducing irritability on the comedown - which would support the idea that serotonin/dopamine balance is a factor - but I just don't have enough experience or knowledge again to say if this is the norm.

Hopefully someone with a solid understanding of amphetamine neuropharmacology can chime in!
All of the structural and functional neuroplasticity in the nucleus accumbens that arises during and mediates the development of an addiction is a result of DeltaFosB overexpression. Since significant DeltaFosB induction only occurs during high dose use or binge use (very high dose use) of addictive drugs, the accumulation of stable, long-lasting phosphorylated DeltaFosB isoforms in the nucleus accumbens is very unlikely to occur in most people at typical doses used in ADHD (oral doses of 5-60 mg). Those isoforms only last in the brain for about two months, so if one's stable/daily pattern of amphetamine doesn't result in compulsive behavior (i.e., an addiction) after two months time, it almost surely never will.
Narcolepsy treatment sometimes involves using amphetamine at markedly higher doses (e.g., 150 mg/day) or alternative routes of administration (e.g., intravenous); obviously, doses that high and IV administration greatly increase the amount/speed (respectively) of drug delivery to the brain and result in higher postsynaptic dopamine signaling in the nucleus accumbens relative to lower doses or oral administration. In those circumstances, there is a risk of DeltaFosB accumulation.

Irritation/irritability is an emotion. Cognitive processing speed, or mental chronometry, isn't really related to emotions.

Excessive dorsal striatal dopaminergic signaling is associated with psychomotor agitation, but that's basically just excessive movement. Based upon the fact that NRIs can cause irritability as a side effects, I'd assume increased NE signaling in one of the noradrenergic pathways in the brain would be responsible for that symptom of amphetamine. It seems plausible that the serotonergic system mediates part of this effect of amphetamine/methamphetamine though. I really doubt there's a dopaminergic component given that DA isn't implicated in regulating emotions unrelated to reward/aversion.
 

Captain.Heroin

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Irritation/irritability is an emotion. Cognitive processing speed, or mental chronometry, isn't really related to emotions.
Arguably incorrect on the last part but it is alright to believe this.

Thank you about the expression of deltafosb, etc very interesting information.
 

som3dankbudz

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I'm writing this while half-asleep and didn't proofread so there may be nonsensical/butchered sentences or typos. Too tired to do that RN.


FWIW, dopamine in the nucleus accumbens regulates motivation in general, not just reward motivation. The NAcc is the most important brain structure in both aversion and reward systems (the former isn't really well researched, but it's very well established the the NAcc is responsible for assigning motivational salience in general and aversive salience [via D2-type NAcc MSNs] and incentive salience [via D1-type NAcc MSNs] in particular). As an aside, the NAcc contains both a hedonic hotspot and a hedonic coldspot and participates in both classical/operant conditioning (e.g., it mediates Pavlovian-instrumental transfer), so it's involved in the regulation of every key function of these systems (i.e., motivation, pleasure/displeasure, and associative learning) as well.



All of the structural and functional neuroplasticity in the nucleus accumbens that arises during and mediates the development of an addiction is a result of DeltaFosB overexpression. Since significant DeltaFosB induction only occurs during high dose use or binge use (very high dose use) of addictive drugs, the accumulation of stable, long-lasting phosphorylated DeltaFosB isoforms in the nucleus accumbens is very unlikely to occur in most people at typical doses used in ADHD (oral doses of 5-60 mg). Those isoforms only last in the brain for about two months, so if one's stable/daily pattern of amphetamine doesn't result in compulsive behavior (i.e., an addiction) after two months time, it almost surely never will.
Narcolepsy treatment sometimes involves using amphetamine at markedly higher doses (e.g., 150 mg/day) or alternative routes of administration (e.g., intravenous); obviously, doses that high and IV administration greatly increase the amount/speed (respectively) of drug delivery to the brain and result in higher postsynaptic dopamine signaling in the nucleus accumbens relative to lower doses or oral administration. In those circumstances, there is a risk of DeltaFosB accumulation.

Irritation/irritability is an emotion. Cognitive processing speed, or mental chronometry, isn't really related to emotions.

Excessive dorsal striatal dopaminergic signaling is associated with psychomotor agitation, but that's basically just excessive movement. Based upon the fact that NRIs can cause irritability as a side effects, I'd assume increased NE signaling in one of the noradrenergic pathways in the brain would be responsible for that symptom of amphetamine. It seems plausible that the serotonergic system mediates part of this effect of amphetamine/methamphetamine though. I really doubt there's a dopaminergic component given that DA isn't implicated in regulating emotions unrelated to reward/aversion.
I didn't know all that about the Nacc being central for motivation; heard through some "downstream" effects many other facotrs can be at play. And of course not "DosforB', but sensitization to amphetamine can occur at therapeutic dosages. I do not believe the sertonergic side of hgiherdose amphetamine or meth dosing handles the noradrenic side to the extent your saying. I believe there is a synergism with the noradrengic side and mild serotonergic actity with higher dose amp or meth(not speaking from experience). Other than that there are more facotors other than monoamine oxidase re specifically noradregic metabolic pathyways. Not to mention; your brains other ways of handling noradrenaline, adrenaline; including the pns. With the side effects from normal or every day, or not higher dose usage(little to know sertonergic activity) the released and metabolized DA-> NE and. Not to mention amphetamine is also a slight da and NE reuptake inhibitor other than being a potent monomine releaser. With little to no sertonergic activity to his amphetamine use; I believe he'll be relying on his old gabanergic system to help regulate that problem. Even if there was any 5-HT activity as with the described use; I dont see that being a factor other than the synergy that other than that... meaning I don't believe any 5-HT mechanisms would handel this NA unless the serotonergic aspect or meth use is involveed and even then. As far stritial dopamine causing psychomotor agititation; not well versed in this being the only complaint surrounded periphreal dopamine. I'm under the impression this release or regulation happens in the hypothalamus? I'd like to know more.
 
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