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direct dopamine agonist?

in the sense that everything in pharmacology is largely bullshit...

care to elaborate on exactly why you think the generalised concept of a human reward pathway (providing comparisons to rat data,) being based on the mesocorticolimbic dopamine system is bunk?

does anyone know of any human studies (neurosurgery etc.) where subjects have actually had electrical stimulation of their VTA?
I had a quick look on pubmed under: "electrical stimulation" AND VTA but didn't find anything. hmm, papers from '2005' are already out.

anyway, the rat data (I havent seen any raw data, actually - just textbook stuff on reward circuits,) seems reasonably convincing... ie, rats self-simulating until death.
why does our analogous pathway not function the same?

how might the other DA pathways contribute?
 
No, not in the sense that everything in pharmacology is bullshit... it's not really anything to do with pharmacology...

It's bullshit in the regard that its an interpretation of data that is only weakly supported, and is generally tested by stupid experiments.

Firstly, the idea that dopamine release in the Nucleus Accumbens is still touted as the most important part of the cognition of pleasure, is generally seen as bullshit these days... unpleasurable stimuli cause the release of dopamine.

But more, the experiment goes "Rat presses button, it gets stimulus in VTA; rat presses button forever". So from that they say, this must be extremely pleasurable... I can think up a litany of other explanations (almost none of them likely, but they still all fit that data). But the one a large amount of people accept these days is that dopamine release facilitates synaptic plasticity... and the the "pleasure circut" is actaully the "positive and negative reward mediated learning circut". The rat keeps pressing the lever because its 'addicted' to it; it's brain has been hijacked into forming an abarant obsession with pressing the lever, just like the addict has wih drugs.

Now there are obviously some links with pleasure and mesolimbic/mesocortical dopamine pathways, buts the idea of VTA --> NAc --> Pleasure, is just retarded.

Read the most recent three papers from this list. Good stuff, from Otago.
 
I am not skilled in phamacology at all so these papers mean nothing to me. As a chemist what I know is that binding to dopamine receptors [ie. displacement of WIN] is only half the story. Once bound, it is also necessary for the ligand to be a potent uptake inhibitor. It is the ratio between these two variables that is considered pivotal in determining whether or not the rat is likely to press the lever. Dopamine and the lever pressing go 'hand in glove' as the most accurate model in predicting whether a drug will be addictive or not. However once the reader gets their head around this concept it becomes apparant that dopamine may not be the only pathway that a drug is stimulating. Say that just because a drug stimulates dopamine release, it may not be addictive if for instance tinnitus and feeling physically sick are side-effects that accompany its administration.
 
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how much l-tyrosine actually becomes dopamine in optimal conditions?
 
so reinforcement is not necessarily mediated by 'pleasure'?

this guy Reynolds is pretty 'core.
nature in 2001, neuroscience in 2002 and j.neurosci in 2004 :)
is he your supervisor?

just was reading the abstracts for those papers. i'm not a physiologist. firing modes etc. go over my head.

are you saying that DA release in the nucleus accumbens from VTA neurons IS an integral part of a putative pleasure circuit but that simply stimulating this pathway does not necessarily directly produce pleasure - merely reinforcement?

i'm thinking about doing my masters on synergistic interactions on reward pathways between cannabinoids and opioids. one of Michelle Glass's PhD students is doing (amongst a few other things) synergism between cannabinoids and opioids in pain pathways and finding some encouraging results. It would be at the signalling level as opposed to the electrophysiological level.
 
OT:
It has occured to me that I need to trudge through an intro psychopharmacology text. My one course in biopsych isn't freaking cutting it. :)

ebola
 
its actually quite cool on this forum to have a good mix of psycho and molecular pharmacology people. i'm firmly entrenched in the molecular aspects myself
 
another tyrosine questions came into my mind-
1)is there any tolerance associated with l-tyrosine?
2)sugestions for best way taking it to increase metabolism to dopamine
 
Reynolds is in Physiology, I want to try and do my PhD with him...

What I'm saying is that the pleasure pathway isn't about pleasure at all, its a learning pathway.

D_DOOD: You're question depends on how you define "optimal conditions". But generally, the answer would be in the fractions of percents... I'd geuss around 0.1% probably less.

Tolerance? Tyrosine under normal situtations doesn't produce any effects to become tolerance too. It's a natural amino acid, it's in your diet every day.
 
Yeah, l-tyrosine is just broken down in the periphery--the BBB aromatic amino acid transporter is already nearly saturated at normal dietary levels. Thus, I doubt l-tyrosine actually helps potentiate indirect DA agonists like amphetamine and methylphenidate, unless an individual has a normally tyrosine deficient diet.

As for direct DA receptor agonists not being "fun." I think that the doses are usually too small to agonize enough D1-like and D2-like receptors. If one were to take a direct agonist at a massive dose, however, I think one would just end up with a lot of side effects (such as severe headache, dizziness and vomiting) and little euphoria. Many of the direct DA antagonists also have some affinity for 5-HT receptors, which could be involved. In addition, there are a number of DA receptor splice variants, presumably dopamine itself has an affinity for all of them, whereas direct agonists likely do not. Finally, while most are quick to say "dopamine = fun," as BliZ0r and others have pointed out, that is way, way too oversimplified a picture to be useful. Not only is the mesolimbic pathway much more sophisticated and unpredictable than a simple "pleasure detector," there are more neurotransmitters involved in "the joy of speed" than just dopamine. What about NA. While NA release by itself is not all that fun (especially the peripheral NA release of ephedrine), I am sure central NA release has a lot to do with the phenomenological effect of amphetamine.
 
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I don;t study this subject, but it seems that defining an "agonist" as a pre-cursor OR a re-uptake inhibitor OR a releasing agent OR a substitute that binds to a receptor is really, really unnecessarilly broad and confusing.

There should be a word for each of those separate things IMO... I always thought an "agonist" was the last item in that list.
 
Optimal conditions? Well if you mean optimal conditions for tyrosine into dopmaine, that would be when you were actaully getting a very small amount of dietary tyrosine, and your brain was completely depleated of dopamine, so that tyrosine hydroxylase activity was high....

But that isn't the optimal condition for enjoying oneself.

No, you're right snakjaw, and agonist IS, under current theories, a chemical which binds to a receptor in its "activte state", hence swinging the equilibrium towards more active receptors.

Those other things are generally refered to as indirect agonists...
 
not fun

it does not sound like somthing I would like. Would this not be like(and or bring on) opiate w/d type feelings??? Yes I think it would.Yes, im thinking with my kboard aloud lol.
 
I don't have the time to do a thorough review of the subject, but this paper is interesting:

Pharmacological stimuli decreasing nucleus accumbens dopamine can act as positive reinforcers but have a low addictive potential
Michela Marinelli, Michel Barrot, Hervé Simon, Claude Oberlander, Anne Dekeyne, Michel Le Moal and Pier Vincenzo Piazza
European Journal of Neuroscience
Volume 10 Issue 10 Page 3269 - October 1998

The pharmacological stimulus decreasing nucleus accumbens dopamine is a kappa agonist, like salvinorin A. This paper showed that rats will self-administer a kappa agonist, but not if they have to work very hard for it. In contrast, they will self-administer a mu agonist (which increases dopamine release) even if they have to work hard for it. The fact that people will smoke and enjoy salvia divinorum is not consistent with the theory that "dopamine equals reward."

The theory I'm partial to is that dopamine is related to the amount of work an organism will put into something. Given a choice between a little bit of food for free, and climbing over a barrier for more food, rats will choose to climb the barrier, unless dopamine transmission is interrupted.
 
^ How does that theory explain the fact that dopamine release can comes before enjoyment, can happen during unpleasant stimuli, is paused during unexpected reward removal, can be trained to happen for stimuli far removed from the reward itself (a bell, that signals a light, that signals a that signals a beep which signals food) and finally the fact that the dopamine release isn't proportional or even related to enjoyment?
 
Would it be a good idea to combine Ritalin (Concerta) with D2/D3 dopamine agonist Trivastal (piribedil) ?
 
*blink* That's a new drug on me? Is it like one of those dodgy french only, imported from mexico ones?
 
Actually Im from Europe, its one of the anti-parkinson drugs, which is also used for depression/anhedonia. It is very similar to Mirapex (pramipexole). And yes, French made it - Servier company ;-) famous because of Survector (amineptine).
But the whole idea - mixing dopamine agonist with Ritalin ?
 
BilZ0r, how is any current theory consistent with all the data? I'm certainly not clever enough to come up with a unifying theory that explains why dopamine has been implicated in so many different behaviors. As to your question, dopamine release is not necessarily decreased during the removal of expected rewards. A microdialysis study using a radial maze task with a 30 minute delay found that PFC DA increased during the test phase of the task, even when the arms were left unbaited. The distinction between neuronal firing patterns and actual transmitter release shouldn't be lost.

Phillips et al. 2004. Magnitude of Dopamine Release in Medial Prefrontal Cortex Predicts Accuracy of Memory on a Delayed Response Task. J. Neurosci. 24(2):547–553.

The reward prediction error theory is also hard to square with the fact that D1 receptors are mostly extrasynaptic. It is starting to seem likely that VTA neurons co-release glutamate, though, which would be well-suited to a reward prediction error function. If it's true that glutamate is serving that function, that leaves open the question of what DA's contribution is.

http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=15309046
 
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