Research about NMDARs and primate brain differences from humans

[Nagelfar]

Someone once, Hamilton? here stated why exactly ketamine and similar type NMDAR antags wouldn't cause olney's lesions in humans, and it had to do with a brain mechanism of how its processed/metabolized that humans had but primates didn't (since olney's lesions occurred in tested primates). Does anyone know what this specific mechanism was? I can't find it in a thread search, but I know it was mentioned (many years ago) here at one time.

 

[anubis23]

I think Olneys Lesions is less likely in humans because, a number of the studies involving its production were either: Direct brain injections or parenteral injection in very young rats, or other weird routes of administration that would definitely not favorably replicate human metabolism.

First we must establish what form, if any of brain alteration is present in cases of abuse of NMDAR antagonists in humans. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713393/
^ A small size of subjects, ludicrous dosages, and its almost impossible to screen for other potential neurotoxins. Please let me know if you guys find any better studies concerning brain examinations in users of NMDA antagonists.

Strangely enough, anecdotally, DXM use produced far less memory and cognitive deficits for me personally ( at the peak of my use I was using it about twice a week, which did not last long as this interfered with responsibilities, I haven't used DXM in a couple years now ) than MXE or Ketamine had produced. I definitely felt more off, slower, and less capable over all with the latter NMDA antagonists. I initially thought it was due to the SRI property of dxm ( see: http://www.ncbi.nlm.nih.gov/pubmed/10812043 ) however since we are not sure of the long term effects of MXE, it may be due to the neuroprotective metabolite 3-HM, NADPH oxidase inhibition, and Sigma-1 agonism that is not present in the other substances.

Sigma-1 agonism and its potential relationship to mitigating neurotoxicity indirectly: http://www.ncbi.nlm.nih.gov/pubmed/9596556

 

[dopamimetic]

I think the Olney's lesions are a really brilliant example for how extrapolation or distortion of scientific results can lead to the wildest theories. Have to admit that I don't remember all of the stuff from these papers, but W. White who publicized that about 'That's your Brain on Dissociatives' based on some reports of cognitive impairments from excessive DXM use even relativized his own work some time later.

Chronic K use can in fact induce some changes in the brain that are visible on a MRI but afaik it's not yet known whether these changes are reversible and I think it's maybe related, but not exactly as theorized. The exact mechanism will yet have to be established. But NADPH oxidase for sure plays a key part, it can produce nasty superoxides -and- lead to overall increase of free glutamate --> more excitation, the superoxides possibly leading to inflammation --> some yet-to-understand cascade involving inflammation markers and possibly quinolinic acid --> more excitation --> eventually excitotoxicity. But this will not happen to the very end in most healthy humans using responsible dosages.

Funny that you mention the NADPH oxidase inhibition just now when I've gone through numerous papers and all that in the last days to understand it's role, in relation to glutamate, to dissociatives (which usually up-regulate the NADPHo with the exception of DXM) and all that ...

Interestingly DXM - about which all the stuff with Olney's lesions has been publicized initially - might actually protect to some degree against that excitotoxicity!!

Do you have any sources about the proposed mechanisms of 3-HM?

 

[anubis23]

Seiko was on to something when mentioning the heat shock protein for the inflammation relation.

https://en.wikipedia.org/wiki/3-Hydroxymorphinan#cite_note-pmid15596482-3

 

[dopamimetic]

Thanks! The last time I've checked the wikipedia page was only a stub

its neuroprotective properties appear result from inhibition of glutamate release via the suppression of presynaptic voltage-dependent Ca2+ entry and protein kinase C activity.

Even another point possibly making DXM safer / different than the usual dissociatives!

 

[anubis23]

PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of fluvoxamine (20 mg/kg/day), but not paroxetine (10 mg/kg/day). Furthermore, the effect of fluvoxamine on PCP-induced cognitive deficits was antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1 mg/kg/day). Moreover, PCP-induced cognitive deficits were also significantly improved by subsequent subchronic (2-week) administration of the selective sigma-1 receptor agonist SA4503 (1 mg/kg/day) or neurosteroid dehydroepiandrosterone 3-sulfate (DHEA-S; 25 mg/kg/day).

http://www.ncbi.nlm.nih.gov/pubmed/16495935

Old topic but as I was studying sigma-1 receptors I thought of the prior discussions here.

 

[WSH]

Someone once, Hamilton? here stated why exactly ketamine and similar type NMDAR antags wouldn't cause olney's lesions in humans, and it had to do with a brain mechanism of how its processed/metabolized that humans had but primates didn't (since olney's lesions occurred in tested primates). Does anyone know what this specific mechanism was? I can't find it in a thread search, but I know it was mentioned (many years ago) here at one time.

As far as I know, it actually did not occur in primates, only in rats:

The unpublished monkey data that we know about, that of Frank Sharp, actually shows that there is no damage at doses up to 10mg/kg.

Maybe you mean the difference between humans and rats, in which case I (or rather Karl) can tell you the different mechanism:

Ketamine is highly promiscuous and eventually binds to the same receptors as some of the protective agents listed above, which shutdown the over-excitement. So the toxic effects happen via one neurochemical system (glutamate) and this is switched off by other systems activated at higher ketamine levels (e.g. the opioid system). In humans, the opioid system (amongst others) cuts in before activation of the glutamate systems reaches the point where cell damage occurs, but in rats this is not the case.