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"Effects of DXM on DA release in NAcc: Interactions with Morphine"

theGirlWithBlueHair said:
You are correct. But it's effect is the same as any NMDA antagonist so remember that !
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Not quite!.. DXM is also a KOR agonist. DXO its main metabolite in humans (and rats! not very different from humans anyway) is even more potent KOR agonist than DXM. The Ki of DXO @ KOR = 1uM about 200 times more potent than NMDA (Ki c 220uM). cf here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930996/
A prototytical potent and selective KOR agonist is Salvinorin A the psychoactive principle of Salvia Divinorum.. Anybody who've ever try Salvia will tell you that dissociation via agonism at Kappa opioid receptors has practically nothing in common with NMDA mediated disso..


Second, Activation of Kappa Opioid Receptors in the claustrum upregulate dopamine D2Rs in the VTA-Nacc area. Chronic (over)stimulation of D2R-rich neurons in that brain region either by mu opiates or psychostimulants like methamphetamine lead to their downregulation..Hence the anti-addictive effect of DXM, Ibogaine and similar other Kappa agonists (which basically rewire the Ventral Tegmental and Nucleus Accumbens by upregulating D2Rs). It might well be that KOR agonism rather than NMDA antagonism accounts for much of the observed effets of DXM.. To reduce DXM/DXO effect to NMDA antagonism alone would be a big mistake imho..




Centrally active KOR agonists have hallucinogenic or dissociative effects, as exemplified by salvinorin A (the active constituent in Salvia divinorum).....


...On the basis of the preceding knowledge, it has been proposed that inhibition of the claustrum (as well as, "additionally, the deep layers of the cortex, mainly in prefrontal areas") by activation of KORs in these areas is primarily responsible for the profound consciousness-altering/dissociative hallucinogen effects of salvinorin A and other KOR agonists.[11][12] In addition, it has been stated that "the subjective effects of S. divinorum indicate that salvia disrupts certain facets of consciousness much more than the largely serotonergic hallucinogen [LSD]", and it has been postulated that inhibition of a brain area that is apparently as fundamentally involved in consciousness and higher cognitive function as the claustrum may explain this.[11] However, these conclusions are merely tentative, as "[KORs] are not exclusive to the claustrum; there is also a fairly high density of receptors located in the prefrontal cortex, hippocampus, nucleus accumbens and putamen", and "disruptions to other brain regions could also explain the consciousness-altering effects [of salvinorin A..blabla blabla...https://en.wikipedia.org/wiki/Κ-opioid_receptor
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I've always thought the claustrum was a fascinating region...

But let us not forget the sigma/SNRI affinities as well.
 
theGirlWithBlueHair said:
No, all NMDA antagonism produces the same effects, regardless of the drug in question
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There are some functional differences between NMDA antagonists depending on how they get stuck in the channel, there is a fair bit of subjective different between high trapping (ketamine) and low trapping (memantine) NMDA antagonists. You'll find Memantine for one tends to have more effects on extrasynaptic receptors which apparently don't really contribute to normal action potential generation much, but may rather modulate network oscillations.
 
Depending on variable blockade of the channel's ion flux due to different binding mechanics of the ligand (slow dissociation, especially slow enough for the antagonist to be blocked in by the Mg) you will see different effects on physiology, and in the case of a drug like memantine that is mostly affecting extrasynaptic NMDAr's, the modulation of network oscillations that is occurring due to blockade of extrasynaptic NMDAr's could be playing a different role than a drug that is mostly affecting synaptic NMDA'rs.
 
Yes, but it is still calcium release, regardless of ligand, calcium is still released. I agree with the variability you are talking about, but they all inhibitcalcium release.
 
I think the original reason why I was nitpicking the differences in NMDA antagonists was so we don't misinterpret study results (With DXM we should definitely hold off on interpretations), so one hypothetical example is if the alterations in network oscillatory activity due to memantine etc. caused a decrease in dopamine in NACC etc. and this outweighed the alteration in synaptic NMDAr function that would normally increase dopamine in NACC, then we should really be careful what interpretation we make off of such a study that deals with more extrasynaptic receptors. In this case with DXM we should mostly be concerned with off target effects though.

Also I just want to say sorry if it feels like you're getting ganged up on around bluelight :( There are definitely a lot of people around here who don't contribute anything useful to the discussions people like you and I would like to have.
 
I think think we might have been stressing slightly different points! sorry for the confusion.

memantine is still going to use calcium to mediate it's effects though.

all I'm trying to do is provide information, and not to he annoying....
 
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