Dopamine antagonists

[rickolasnice]

Why do dopamine (or any other "euphoric" neurotransmitter) antagonists not cause a low followed by a high - Like the opposite of a comedown?

Wasn't sure if this is ADD material but wanted your answers

 

[Zombie Pharmacist]

I think because dopamine doesn't regulate mood like serotonin, a deficiency is more likely to manifest itself as increased hunger, changes in memory, loss of motivation and apathy amongst other things - all of which are seen with dopamine antagonists (such as many antipsychotics). The removal of such antagonist generally leads to the opposite - such as weight loss, over motivation, restlessness and so on.

 

[rickolasnice]

But straight up DA agonists cause pleasure etc.. And the comedown causes lack of.. why doesn't work the other way round?

 

[sekio]

You're greatly oversimplifying - dopamine agonism does not always cause pleasure. See for instance, ergoloid dopamine agonist drugs. There's a lot more to human moods than "if you have lots of dopamine you are happy".

Generally the drugs you'd think of as "releasing dopamine" also have other effects that play a part in the reinforcing effects. For instance, if you block the norepinephrine release of MDMA, it is no longer stimulating and euphoric. There's just too many factors at play here.

 

[TCMVegas]

Generally the drugs you'd think of as "releasing dopamine" also have other effects that play a part in the reinforcing effects. For instance, if you block the norepinephrine release of MDMA, it is no longer stimulating and euphoric. There's just too many factors at play here.

Source??

This is contrary to what I had believed. Ethylphenidate and methamphetamine are the most selectively dopaminergic drugs I can think of immediately, and as a result both are very very pleasurable.

 

[Toucan]

Ethylphenidate and methamphetamine are the most selectively dopaminergic drugs I can think of immediately, and as a result both are very very pleasurable.

They're not selective for dopamine, both of them release/inhibit reuptake of noradrenaline also...
I think OP raises a valid point though, perhaps a better example would be the same principle but applied to the opioid receptor?

 

[TCMVegas]

From wikipedia: Methylphenidate vs Ethylphenidate binding affinities

Compound[5] Binding DAT Binding NET Uptake DA Uptake NE
d-TMP-------- 139 ------ 408 ------- 28 ----- 46
d-TEP --------276 -------- 2479 ----- 24 ----- 247
dl-TMP-------- 105 --------- 1560 ------- 24 ----- 31
dl-TEP-------- -382 ------- 4824 ------ 82 ----- 408

I'd argue that in the case of Ethylphenidate, it's REDUCED affinity for NE makes it more pleasurable... doesn't this seem like the obvious answer? Less NE activity = less side effects preventing you from reaching higher doses and therefore higher DA levels... I can say from experience that ethylphenidate is a very 'Good' feeling drug.

Sure, it's technically an NDRI, but ethylphenidate is the MOST SELECTIVE dopaminergic drug that I know of. I think of it as showing users what DA feels like, which is cool IMO.

I don't see any evidence of the statement made earlier, but please prove me wrong

 

[endotropic]

They're not selective for dopamine, both of them release/inhibit reuptake of noradrenaline also...
I think OP raises a valid point though, perhaps a better example would be the same principle but applied to the opioid receptor?

For the opiate receptors there's not a whole lot of activity under normal circumstances, so just blocking the receptor doesn't really take you any lower. Just blocking the infrequent inactivation isn't enough to cause any sort of rebound effect.

 

[endotropic]

From wikipedia: Methylphenidate vs Ethylphenidate binding affinities



I'd argue that in the case of Ethylphenidate, it's REDUCED affinity for NE makes it more pleasurable... doesn't this seem like the obvious answer? Less NE activity = less side effects preventing you from reaching higher doses and therefore higher DA levels... I can say from experience that ethylphenidate is a very 'Good' feeling drug.

Sure, it's technically an NDRI, but ethylphenidate is the MOST SELECTIVE dopaminergic drug that I know of. I think of it as showing users what DA feels like, which is cool IMO.

I don't see any evidence of the statement made earlier, but please prove me wrong

Does anyone have an explanation for how these drugs inhibit DA/NE reuptake at ~1/10th the concentration that they bind the respective transporter? I'm having trouble wrapping my head around that one.

 

[sekio]

source for reboxetine (NRI) reducing stimulatory f/x of MDMA in humans.
http://www.nature.com/clpt/journal/v90/n2/full/clpt201178a.html

Reboxetine reduced the effects of MDMA including elevations in plasma levels of NE, increases in blood pressure and heart rate, subjective drug high, stimulation, and emotional excitation. These effects were evident despite an increase in the concentrations of MDMA and its active metabolite 3,4-methylenedioxyamphetamine (MDA) in plasma.

Ethylphenidate and methamphetamine are the most selectively dopaminergic drugs [...] I can say from experience that ethylphenidate is a very 'Good' feeling drug.

Not everybody shares your sentiment. And methamphetamine is a terrible example of a selective drug... it releases NE/DA/5HT as well as interfering with glutamate and a bunch of other shit.

I don't think there even exists a drug that is 100% selectibe for DA over NE. Maybe DATScan or something. I don't hear of people abusing PET scanning drugs though.

 

[specialspack]

Source??

This is contrary to what I had believed. Ethylphenidate and methamphetamine are the most selectively dopaminergic drugs I can think of immediately, and as a result both are very very pleasurable.

Pfft, nonsense. a) most anecdotal evidence suggests people find methylphenidate more pleasurable than ethylphenidate.
b) methamphetamine is not that selective for dopamine.

 

[TCMVegas]

Pfft, nonsense... methamphetamine is not that selective for dopamine.

lol, you guys got me x.X

the only dopamine antagonist I've taken is risperidone, and it effectively made me sleepy for 18 hours, basically not wanting to move or think or do anything but be brain dead on the couch. Not highly recommmended. I took 3 of them one time, which is supposedly a reasonable dose, and sometimes now have muscle spasms in my legs, which are very mild. This is as a warning to anybody considering DA antagonist experimentation, that tardive dyskinesia exists, and I might* have it from that seemingly low-risk event. It usually only happens when I'm on stimulants, but particularly modafinil. Can't say that I understand why that would be. Possibly GABA antagonism I suppose.

 

[rickolasnice]

OK.. so say you take a NE, 5-ht and DA antagonist.. would the "comedown" then be a high?

(Sorry for ignorance.. I've been wondering this for a while and can't find any info out there on the www)

 

[sekio]

Not as such, no.

 

[MeDieViL]

Why do dopamine (or any other "euphoric" neurotransmitter) antagonists not cause a low followed by a high - Like the opposite of a comedown?

Wasn't sure if this is ADD material but wanted your answers

Because da doesnt cause euphoria.

 

[TCMVegas]

Because da doesnt cause euphoria.

You guys keep saying that, but I don't believe you. Like, at all.

Sekio's link about NE-mediated interference with MDMA's "subjective drug high, stimulation, and emotional excitation", doesn't support that notion either. Blocking the "speedy" part of an amphetamine high seems likely to decrease the "subjective high". But that's far from saying that DA doesn't feel good. It just means that NE can contribute to a high...

 

[MeDieViL]

Its very complex and involves rythmic firing of differened neurotransmitters but ultimately it comes to mu.

My high dose risperdal with amphetamine (ad first abolishes euphoria) but then the addition of phenibut makes amp work like i didnt take risperdal (at doses that block pretty much all da receptors more potent then da itself) its all very complex, da plays a role but isnt the end of the "cascade".

 

[sekio]

You guys keep saying that, but I don't believe you. Like, at all.

Would you like to provide some evidence? There is plenty pointing towards DA not being the end-all be-all of reward.
Some things to consider -
D/A release in the Nacc is greatest when there is only a 50% chance that the actions being performed will cause reward - that is, reward is greatest when randomly associated with e.g pressing a button. If you make a stimulus produce a reward 100% of the time, DA release stops happening. This explains why gambling and risky activities are considered rewarding.

Intravenous DA is used to combat hypotension. Nobody finds it pleasurable.

There exist dopamine direct agonists in huse that activate dopamine receptors selectively. None of them in popular use are considered to be "euphoric" or "abusable".

Most drugs of abuse are not selective DA releazsers/reuptake inhibitors, they also have activity at the other monoamines or mu-opioid. DA-preferential releasers (ethylphenidate) generally are considered "less euphoric" than balanced release agents/releasers (cocaine, mephedrone).

 

[x264]

cingulate cortex response to pramipexole (Fig. 1C) may provide a functional basis for studies linking anxiety and depression with dopamine (7, 8, 29, 48, 50–52) and cingulate cortex (53–55). Patients with major depression have decreased rCBF, metabolism, and volume of subgenual anterior cingulate cortex (54, 56), and postmortem studies in depressed patients show loss of glia in this region (57). Anterior cingulate cortex is innervated by thalamic neurons that are influenced by ventral striatum (58, 59), and dopamine release in the D3R-rich ventral striatum correlates with amphetamine-induced euphoria

Dopamine does cause euphoria.

Fig 1.

You guys keep saying that, but I don't believe you. Like, at all.

Sekio's link about NE-mediated interference with MDMA's "subjective drug high, stimulation, and emotional excitation", doesn't support that notion either. Blocking the "speedy" part of an amphetamine high seems likely to decrease the "subjective high". But that's far from saying that DA doesn't feel good. It just means that NE can contribute to a high...

 

[MeDieViL]

Selegiline and ldopa with cardidopa pretty much proof just da doesnt feel good, while increasing endorphines would feel good.