NMDA-Antagonism & Dopamine reuptake inhibiton

[ungelesene_bettlek]

Dear expert psychopharmacologists,

after all the years, I am still wondering: is it true that NMDA-antagonism by arylcyclohexylamines via the PCP binding site of the glutamate receptor is intrinsically tied to dopamine reuptake inhibition? If so, how does it come?

Please explain it to me in laymen's terms (i.e. I do hold a MSc degree and almost a PhD in a "hard" scientific field, but unfortunately not in pharmacology).

Sincerely yours,
your nosy researcher

PS: See this 4.5 year old thread by me in the ADD archive: dissociatives / arylcyclohexylamines pharmacology

 

[serotonin2A]

The two effects are not linked. Some compounds bind to NMDA-R and DAT, whereas others are more selective. For example, MK-801 is selective for the PCP site and BTCP is selective for DAT.

 

[ungelesene_bettlek]

@serotonin2A: OK, thank you for clearing up that misconception of me! I always thought someone here told me it was so sometimes, but then I was obviously mistaken.

But nevertheless, many arylcyclohexylamines are both, or aren't they?

 

[serotonin2A]

Yes, many arylcyclohexylamines have multiple pharmacological effects, including inhibition of dopamine uptake and blockade of NMDA receptor currents.

 

[ungelesene_bettlek]

@serotonin2A: OK, thank you for clearing that up. But that I know already (see my old thread linked above). I also know now that methoxetamine has also significant action as serotonin reuptake inhibitor, which is probably also crucial for it being even more recreational/addictive/"moreish" than ketamine to many people.

Is it possible that also tiletamine is pretty weak as DRI, at least much weaker than ketamine? I have heard that sometimes tiletamine is sold as ketamine on the UK black market, and people generally consider it is a "hole without fun".

On the other side, can we say more now on how important the mu opioid receptor agonism is in the psychopharmacological action of the dissociative arylcyclohexanamine?

 

[serotonin2A]

The SERT issue is something that people like to speculate about but it doesn't necessarily make a lot of sense when you think about it. There is a rapid-acting SSRI called duloxetine that people take and I've never heard it described as being fun, either taken alone or in combination with recreational drugs. There is no evidence that acute inhibition of serotonin uptake has any positive effect on mood. And usually serotonergic effects REDUCE compulsive drug use.

Regarding mu agonism, none of the popular arylcyclohexylamines bind to mu, so it doesn't seem to play a direct role in mediating their effects.

 

[Zilpe]

I was under the impression that most of the well-known recreational arylcyclohexylamines have no affinity for DAT but are instead often direct agonists of dopamine receptors.

 

[serotonin2A]

I was under the impression that most of the well-known recreational arylcyclohexylamines have no affinity for DAT but are instead often direct agonists of dopamine receptors.

That isn't correct. The only researcher that has ever reported that arylcyclohexylamines bind to D2 is Philip Seeman. No one else can replicate his results with arylcyclohexylamines or other compounds. For example, see the following studies:

http://www.ncbi.nlm.nih.gov/pubmed/19755662
http://www.ncbi.nlm.nih.gov/pubmed/20506301
http://www.ncbi.nlm.nih.gov/pubmed/16730695

It is pretty well established that arylcyclohexylamines such as PCP and TCP bind to DAT. The binding of radiolabled TCP and PCP to membranes in brain homogenates was studied extensively in the 1980's and 1990s and two binding sites were identified, which were called PCP site 1 and PCP site 2. Site 1 is equivalent to the PCP site in the NMDA channel and site 2 is now recognized as being part of DAT.

See:
http://www.ncbi.nlm.nih.gov/pubmed/1320214
http://www.ncbi.nlm.nih.gov/pubmed/1671086
http://www.ncbi.nlm.nih.gov/pubmed/7968938
http://www.ncbi.nlm.nih.gov/pubmed/8134901

 

[ungelesene_bettlek]

Thank you very much for your feedback, serotonin2A and Zilpe - I'll do my best to read at least as much of the ncbi.nlm.nih.gov links serotonin2A kindly provided me, and then start posting further questions here, if there are any ones left to me.

 

[Nagelfar]

In terms of DAT reuptake affinity; have there been any way to measure if it acts more like Mazindol, GBR, Benztropines; or like the cocaine, methylphenidate, as certain recent publications seem to purport a very distinct difference in habituation between those two groups (e.g. the former dysphoric and the latter euphoric)

 

[serotonin2A]

In terms of DAT reuptake affinity; have there been any way to measure if it acts more like Mazindol, GBR, Benztropines; or like the cocaine, methylphenidate, as certain recent publications seem to purport a very distinct difference in habituation between those two groups (e.g. the former dysphoric and the latter euphoric)

Yes, there do seem to be pharmacological differences between DAT inhibitors. The following explanations have been proposed:

> Binding to different sites on DAT, or preferential binding to inward vs. outward conformations
> Different effects on DAT phosphorylation
> Different kinetics or rate of onset of DAT blockade
> Modulation by effects on sigma-1 receptors
> Secondary anticholinergic effects of benzotropine are dysphoric

I'm not sure if PCP has ever been compared to cocaine vs. benzotropine. But it is very possible that BTCP has been tested and those findings are likely relevant to PCP.

 

[dopamimetic]

I have recently read a paper suggesting that cocaine and methylphenidate are not just DAT antagonists, but behave more like sort of inverse agonists or atypical releasers - causing activity-dependent reversal of the transporter and overall increased firing speed (vs continued reversal and slowed firing by amphetamine-like compounds). Thus they bypass the auto receptors which would limit the efficacy of a regular reuptake inhibitor (like it is suggested to be the case with SSRIs).

Also cocaine and methylphenidate are sigma-1 agonists, and MPH further probably agonizes 5-HT1a.

Off-topic, I suspect dextromethorphan to exhibit a similar action on SERT.

 

[ungelesene_bettlek]

I have recently read a paper suggesting that cocaine and methylphenidate are not just DAT antagonists, but behave more like sort of inverse agonists or atypical releasers - causing activity-dependent reversal of the transporter and overall increased firing speed (vs continued reversal and slowed firing by amphetamine-like compounds). Thus they bypass the auto receptors which would limit the efficacy of a regular reuptake inhibitor (like it is suggested to be the case with SSRIs).

That sounds exciting, please tell us more!

Also cocaine and methylphenidate are sigma-1 agonists

Interesting. Anyone has already figured out what the sigma recepters are actually all about?

and MPH further probably agonizes 5-HT1a.

Do you think this significantly contributes to its overall action?

Off-topic, I suspect dextromethorphan to exhibit a similar action on SERT.

IMHO DXM is less off-topic in a dissociative thread than cocaine and MPH.

 

[aced126]

DXM combined with SSRIs can result in serotonin syndrome which could suggest it to have the effect on SERT.

 

[dopamimetic]

That sounds exciting, please tell us more!

This seems to be the base paper proposing the inverse agonist hypothesis. There was a longer article somewhere with graphs comparing MPH, d-Amph and sibutramine (probably not the best example for a pure RI imho) but the MPH graph looks exactly like amphetamine in the dose-linear DA increase which is not the case with other reuptake inhibitors. I'll post the link if I find it again of course (maybe here but it doesn't load at the moment.)

Do you think this significantly contributes to its overall action?

With 5-HT1a I'm unsure, just read that off wikipedia - previously it has been suggested that MPH binds to 5-HT2b which sounded alarming in regard of linked pulmonary hypertension and heart valve damage, but at least in 2006 it wasn't known if it's an agonist or antagonist so it might be the latter.
5-HT1a agonism has a bunch of positive effects that would likely contribute to the overall tolerability and alleviate some of the stimulant related side effects, if the activity is strong enough at relevant dosages.
Buspirone (a 5-HT1a partial agonist used for anxiolysis) was completely useless for me but I guess it's just too weak. Looking forward to try cannabidiol. Methylphenidate has robust anxiolytic and mood lifting qualities for me, with for example a-PVP being more anxiety-inducing, so there might be something. Also I don't like the effects of the isolated d-isomer (Focalin) which interestingly has prominent NET affinity so l-MPH can't be as inactive as thought… wonder if it's an interaction-only thing or if l-MPH alone would be even better than the racemate, think I've read that it has a slightly longer half life than the d-isomer, so this remembers me of isopropylphenidate which I'd like to see available for ADHD treatment instead of that shitty Focalin.

Here is the sigma-1 related paper with suggested effects.

DXM combined with SSRIs can result in serotonin syndrome which could suggest it to have the effect on SERT.

It binds relatively strong to SSRI indeed in comparison of it's overall affinities.