direct dopamine agonist?

[Smyth]

Cocaine works in this order (strongest first): NET>SERT>DAT. Common knowledge is that ritalin works on NET and DAT but not SERT. This has something to do with the fact that correct implementation of steric bulk around the nitrogen tends to block access to the SERT receptor, although still allowing a gateway to the other receptors. However this is a very simplified model.

 

[ebola?]

wait...coke works on serotonin more effectively than dopamine???

 

[Smyth]

Yeah, although if you take coke, and turn it into the phenyltropanes, this beefs DAT up a bit and dumbs down SERT. Cutting edge research has pointed towards serotnin as playing a role in cocaines addictive potential (but the results are unclear). I think they took SERT knockout mice and found that cocaine was less addictive in these subjects.

 

[BilZ0r]

I think smyth is over stating it... the differences in potencies depend on what you read... I think theres more evidence that in practicle terms its more like NET>SERTAT.... (though of course it does have a slightly higher affinity for SERT, just how much higher depends on what you read)

 

[ebola?]

I know it is a bit naive to try to infer the subjective feel of a drug from over-arching neuromodulatory effects...but why doesn't coke make you feel like you're "rolling"?

ebola

 

[bandido]

roll

what do you mean dude? If been on several 3 day rolls!!! LOL, joke.

 

[BilZ0r]

The difference between reuptake inhibition and amphetamine like effects... i.e. Uptake inhibitors are essentially impulse dependent, they only cause an increase in monoamine levels where there were monoamines being released in the first place (and to a much lower level, 150-200% increase as against 500-1000%)... Also, MDMA goes SERT~=NET>DAT as opposed to coke's NET>SERTAT.

 

[ebola?]

>>The difference between reuptake inhibition and amphetamine like effects... i.e. Uptake inhibitors are essentially impulse dependent, they only cause an increase in monoamine levels where there were monoamines being released in the first place (and to a much lower level, 150-200% increase as against 500-1000... Also, MDMA goes SERT~=NET>DAT as opposed to coke's NET>SERT:DAT.>>

This makes sense, although cocaine's reuptake-inhibition of these monamines appears to add up to an amphetamine-like subjective experience...which doesn't quite fit into whatever picture I've got in my head...I also was under the prior impression that MDMA affected nor-epi' more than 5ht....but you learn something every day.

ebola

 

[Kandy K]

I read somewhere that Parkinsons patients had been abusing L-dopa, ie taking large dosages of the stuff (12g). It is totally true that increased dopamine is the internal cue that governs drug addiction.

I was under the impression that low serotonin levels is what induces craving...are you saying that increased dopamine is the cause of this? Are the two correlated somehow, or is there another study I can read up on this?

 

[BilZ0r]

also was under the prior impression that MDMA affected nor-epi' more than 5ht

Yeah, I used to think that too... but I doubt it... they'll be close; the potency.

I take back what I said about coke above... Coke is essentially mixed.. it hits up all transporters relatively equally... it really depends on who you read. While (+/-)Meth is NET>DAT>>SERT...

 

[awatkins]

so to conclude, cocaine is not a direct dopamine antogonist?, perhaps my abnormal psychology professor was teaching a myth? or maybe she just meant to say that dopamine levels are affected the most in relation to norapenephrine and serotonin levels?i am confused

 

[ebola?]

We've covered this in the thread a couple times already.

2 key definitions:

DIRECT agonist: causes an increase in the firing of neurons with a particular receptor type by "mimicking" the endogenous ligand for that receptor and fitting directly into the receptor for that ligand.

agonist: increases the activity of a neuron with a particular type of receptor, no matter how.

ebola

 

[C6H6]

^ No, I don't think so.

A (direct) agonist triggers the same cellular events as the natural ligand does, by binding to the receptor. This effect must by no means be an increase in the firing of neurons.

An INDIRECT agonist increases the concentration of the natural ligand at the receptor by mechanisms such as inhibition of reuptake, metabolism or increased release.

The term indirect agonist is not commonly used any more, but replaced by the specific action. Cocaine would better be called an inhibitor of dopamine reuptake (and to a lesser degree of 5-HT and NE), rather than an indirect dopamine agonist. Apomorphine is an example of a (direct) dopamine agonist, but the "direct" is redundant really.

 

[ebola?]

>>A (direct) agonist triggers the same cellular events as the natural ligand does, by binding to the receptor. This effect must by no means be an increase in the firing of neurons.>>

Ummm...I think we just said the exact thing in different words.
As for the increase in firing...I meant an increase elecited by the agonist in comparison to a condition where there is no receptor binding whatsoever...I did not mean to say that direct agonists increase the effect of the edogenous ligand, etc...

ebola

 

[Dr. Beat]

I know it is a bit naive to try to infer the subjective feel of a drug from over-arching neuromodulatory effects...but why doesn't coke make you feel like you're "rolling"?

ebola

I used to wonder about that too because i had read a few years ago they both cause an increase in seratonin, dopamine and noradrenaline in the brain synapse so why dont they feel the same ?

I think they hit lots of different receptors to give a different feeling.

From what i read, coke blocks 5HT3 receptors, and coke does something to sigma receptors.

Where as MDMA hits 5HT2 receptors, histamine receptors, and others.

Alot of people on here say that they dont have much effect cause MDMA has 100 times more affinity for transporters than receptors, but it FEELS alot different to me than coke.

Also methamphetamine seems to block NMDA receptors, (the main glutamate receptor) so that makes it feel different again.

This is a very good site all about this:

http://www.neurotransmitter.net/drugmechanisms.html

 

[BilZ0r]

Alot of people on here say that they dont have much effect cause MDMA has 100 times more affinity for transporters than receptors, but it FEELS alot different to me than coke.

Both those statements are correct. They drugs feel different because they have massively different pharmacology. Even if we were going to ignore the fact that MDMA is primarily serotonin and dopamine transporter specific, while cocaine is pretty much mixed... cocaine is a transport inhibitor, while MDMA is an amphetamine.

Ummm...I think we just said the exact thing in different words.
As for the increase in firing...I meant an increase elecited by the agonist in comparison to a condition where there is no receptor binding whatsoever...I did not mean to say that direct agonists increase the effect of the edogenous ligand, etc...

Why C6H6 took exception was because your comments implied that all agonists increase neuronal firing

 

[ebola?]

>>Why C6H6 took exception was because your comments implied that all agonists increase neuronal firing>>

Oh...whoops. I forgot about endogenous transmitters that reduced the likelihood of an action potential.

ebola