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Dopamine depletion does not alter the mood elevating effects of amphetamine

MeDieViL

MeDieViL

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9) Leyton M, aan het Rot M, Booij L, Baker GB, Young SN, Benkelfat C
Mood-elevating effects of d-amphetamine and incentive salience: the effect of acute dopamine precursor depletion.
J Psychiatry Neurosci. 2007 Mar;32(2):129-36.
OBJECTIVE: Midbrain dopamine transmission is thought to regulate responses to rewarding drugs and drug-paired stimuli; however, the exact contribution, particularly in humans, remains unclear. In the present study, we tested whether decreasing dopamine synthesis, as produced by acute phenylalanine/tyrosine depletion (APTD), would alter responses to the stimulant drug, d-amphetamine. METHODS: On 3 separate days, 14 healthy men received d-amphetamine (0.3 mg/kg, given orally) plus a nutritionally balanced amino acid mixture, the phenylalanine/tyrosine-deficient mixture or the phenylalanine/tyrosine-deficient mixture followed by the immediate dopamine precursor, L-DOPA (Sinemet, 2 x 100 mg/25 mg). Responses to these treatments were assessed with visual analog scales, the Profile of Mood States, and a computerized Go/No-Go task. RESULTS: d-Amphetamine elicited its prototypical subjective effects, but these were not altered by APTD. In comparison, APTD significantly increased commission errors on the Go/No-Go task and did so uniquely in conditions where subjects were rewarded for making correct responses; this effect of APTD was prevented by L-DOPA. CONCLUSIONS: Together these results support the hypothesis that, in healthy men, dopamine is not closely linked to euphorogenic effects of abused substances but does affect the salience of reward-related cues and the ability to respond to them preferentially.
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Full text can be found here.
http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-32/issue-2/pdf/pg129.pdf

Its a study from 3 years ago, but dont think it has been posted here yet.
 
Yeah, trace amines, serotonin affinity, there are many factors involved in amphetamine action. One day they may find that dopamine has nearly nothing to do with the euphoria (just being rhetorical here, but it's interesting to think about.)
 
We know that serotonin affinity is NOT key with amphetamine. What we'd want to compare are the reinforcing effects of NE release versus the reinforcing effects of NE and DA release. People aren't quite clamoring to dose ephedrine or even better, ethcathinone, are they?

ebola
 
Nagelfar said:
Yeah, trace amines, serotonin affinity, there are many factors involved in amphetamine action. One day they may find that dopamine has nearly nothing to do with the euphoria (just being rhetorical here, but it's interesting to think about.)
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Actually, they allready know that;). It does play a role but it isnt the major player as first tought.
The debate over dopamine's role in reward: the case for incentive salience.
Psychopharmacology (Berl). 2007 Apr;191(3):391-431.
INTRODUCTION: Debate continues over the precise causal contribution made by mesolimbic dopamine systems to reward. There are three competing explanatory categories: 'liking', learning, and 'wanting'. Does dopamine mostly mediate the hedonic impact of reward ('liking')? Does it instead mediate learned predictions of future reward, prediction error teaching signals and stamp in associative links (learning)? Or does dopamine motivate the pursuit of rewards by attributing incentive salience to reward-related stimuli ('wanting')? Each hypothesis is evaluated here, and it is suggested that the incentive salience or 'wanting' hypothesis of dopamine function may be consistent with more evidence than either learning or 'liking'. In brief, recent evidence indicates that dopamine is neither necessary nor sufficient to mediate changes in hedonic 'liking' for sensory pleasures. Other recent evidence indicates that dopamine is not needed for new learning, and not sufficient to directly mediate learning by causing teaching or prediction signals. By contrast, growing evidence indicates that dopamine does contribute causally to incentive salience. Dopamine appears necessary for normal 'wanting', and dopamine activation can be sufficient to enhance cue-triggered incentive salience. Drugs of abuse that promote dopamine signals short circuit and sensitize dynamic mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Such drugs interact with incentive salience integrations of Pavlovian associative information with physiological state signals. That interaction sets the stage to cause compulsive 'wanting' in addiction, but also provides opportunities for experiments to disentangle 'wanting', 'liking', and learning hypotheses. Results from studies that exploited those opportunities are described here. CONCLUSION: In short, dopamine's contribution appears to be chiefly to cause 'wanting' for hedonic rewards, more than 'liking' or learning for those rewards. [PubMed Citation] [Order full text from Infotrieve]
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Does amphetamine exisit as a endogenous metabolite of dopamine and or phenylethylamine in the human brain?

I dont believe that the binding of dopamine to its receptors has the significant effect it is portrayed to have. Their affects.....
D1 increased synaptic nmda receptors via trafficing from extrasynatpic sites (major nootropic)with an associated increase in cAMP
D2 causes a stablisation of NMDAr at current site with an associated decrease in amp
D3 havent learnt yet
d4 methylation (is amphetamine (2-methylated) phenylethylamine)
Many articles however use these receptors in a conceptual sense to portray effects of ligands as causes. Therefore something that acts through "Sigma-2"("opiod" amphetamines mode of actions) causes an increase in metabolisms which cause slight negative feedback through D2 to maintain nmda function. and this is called a D2 agonist!!!!!!! when it increases metabolism and synaptic trafficing.

But dopamine is mainly the begining of a cascade onto 3 or 4 ring metabolites that bind to the "sigmas" and a very wide array other targets. If you look a pharamecuticals you will often find dopamine tucked away in there.

If you want proof your going to need to find it for yourself but for a start why dont you imagine binding phenylethylamine to denryl senigile. Whats ifenprodil?
 
The body methylates amphetamine to methamphetamine so why not methylate phenylethylamine to amphetamine?
 
Advaneuro said:
The body methylates amphetamine to methamphetamine so why not methylate phenylethylamine to amphetamine?
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If the body methylates amphetamine to methamphetamine (does it? I've never heard of this before), that's adding a methyl to an amine, which is not that uncommon of a biochemical reaction. PEA to amphetamine requires methylation of a carbon, which is a very different reaction.
 
DA depletion does not alter the mood elevating efffects of amp

That's b/c amp is a false neurotransmitter for DA.
 
Dios Mio! Look at their chemical structures, and do some basic research into the older literature.
 
Dresden said:
Dios Mio! Look at their chemical structures, and do some basic research into the older literature.
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If what you are saying is true those subjects getting the APTD mixture shouldnt get problems with identifying reward. It may act as a dopamine mimetic but there definatly should be a significant reduction in the mood elevation.
 
Both cocaine and amphetamine bind to ol-factory receptors, does ol-factory receptor agonism emulate human phermone type action and adjunct euphoria associated therewith potentially? Are their substances which are just ol-factory receptor agonists?
 
Things to consider:

1)According to the information given, the 14 male subjects were givin an equivelent dose of amphetamine on 3 seperate days. It does not state, however, how much time passed between the "3 seperate days." If the subjects were administered d-amphetamine on three consecutive days, they would have already developed a significant tolerance to the drugs effects (the dopamine effects-please correct me if im wrong-more so than the norepinepherin effects)

2)Euphorogenic effects? THis is a vague term. DOes this mean Ecstasy(serotonin), excitability (norepinephrine), or the feeling of accomplishment (Dopamine). If he is stating that euphorogenic effects are the effects sought after and enjoyed by the user, imo, he is much misled. If he was correct, people on the street would be asking for ritalin, which accoring to him would have significant "euphorogenic effects", instead of d-amphetamine. If "euphorogenic effects" are the effects which inspire euphoria in d-amphetamine users, which-unless im alone on this one-is the feeling of worth and success which seemingly radiates through the cerebrum and across the body after thinking worthy thoughts, doing worthy things, being complimented for good work, and the winning of others admiration via productivity, then the "euphorogenic effects" ARE a result of dopamine.

I despise vagueness and misconception,

sincerely,
forensic bob
 
2)Euphorogenic effects? THis is a vague term. DOes this mean Ecstasy(serotonin), excitability (norepinephrine), or the feeling of accomplishment (Dopamine).
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What about increased libido? That is the predominant euphorogenic effect I get with cocaine and Ritalin (once tolerance is developed to Ritalin that effect goes away). It's been a while since I was prescribed any amphetamine so I can't comment on that one. Either I'm a physiological anomaly or those geeks doing research are too embarrassed to focus on libido.
But then again I get a "raised eyebrow" response whenever I bring up the connection between libido and dopamine .
 
Surprise surprise! After everything had been said and done, we still go back to square one: that in a single molecule the truth resideth not. 8)
 
I'm sorry if this is a bit off topic, but I have recently switched from Suboxone to Opana and have been on Adderall the whole time. I went from doing 60 mgs a day to now switched to Dexedrine and can only do max 15 mgs a day and unless I have to take it to stay up (I have Narcolepsy I have had it way before Opiates were involved) I don't take it. I have lost all euphoria from it and only get speedy peripheral effects. The reason I think its relevant is my mood elevating effects from amphetamines over the last two years have slowly declined. Anyone know what mechanics would be behind this?
 
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