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Syntheso

Why NMDA antagonism?

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Sorry to barge in without having read the thread, but I'd like to contest this;

I've never had a traumatic trip experience (and I've taken hallucinogens countless times), nonetheless I have HPPD. I got it gradually from a long series of mostly enjoyable trip experiences.

Yes, same for me. But, I still had lots of 'big trips' which were a big deal on the mind, a trauma in a sense. Just because I didn't freak out and managed to hold it together, doesn't mean it's not a trauma (I think). Many people with HPPD got it through genuinely traumatic trip experiences though. Just because we didn't have any negative trips, doesn't mean that fear/anxiety circuit is not involved (which I believe, most definitely is).

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Yes, same for me. But, I still had lots of 'big trips' which were a big deal on the mind, a trauma in a sense. Just because I didn't freak out and managed to hold it together, doesn't mean it's not a trauma (I think). Many people with HPPD got it through genuinely traumatic trip experiences though. Just because we didn't have any negative trips, doesn't mean that fear/anxiety circuit is not involved (which I believe, most definitely is).

You may be right :-) Your defense of the idea does sound a bit 'ad hoc' though (i.e. where's the falisifiability if a counter example can always be construed to fit the theory?).

Not trying to be polemic here, I look forward to read the thread thoroughly. :-)

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You may be right :-) Your defense of the idea does sound a bit 'ad hoc' though (i.e. where's the falisifiability if a counter example can always be construed to fit the theory?).

Not trying to be polemic here, I look forward to read the thread thoroughly. :-)

You're right, it's not a strong response. I will write you something more detailed when I get a chance. A better response to your point though is that psychedelics are considered emotional amplifiers. They somehow exaggerate external stimuli and your feelings. Whether or not you have a good or bad trip, the brain isn't quite geared for such intense amplification of its stimuli, or,  in HPPD brains, at least. So, even if the trip is not subjectively negative, the brain obtains HPPD when it can't process the intense stimulus and feelings that go with it; I suggest the fear/anxiety circuit is invoked here, in a flight/fight response to the aggressive stimuli. I imagine there is some sort of cellular litter that needs to be processed, as trauma in PTSD requires. 

I need to revise the thread, really. I can see that NMDA antagonists would be useful when someone's HPPD is quite severe, protecting further damage. In cases where people are recovering I am not sure it's a good idea - I think that receptor is required to be unblocked to process the emotional 'trauma'. 

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Is the nmda antagonist good or bad for HPPD? Conclusion.

My conclusion is:

- Good for preventing further damage in aggressive HPPD, NMDA antagonists are neuroprotective

 

but

 

- NMDA antagonists might block the potential to heal through NMDA-mediated fear extinction (as argued in this thread)

- NMDA antagonists produce memory deficits (the NMDA receptor is key in memory and synaptic plasticity)

- NMDA antagonists produce schizophrenic-like effects at certain doses (ketamine and PCP are NMDA antagonists)

"NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of diseases including stroke and neurodegenerative disorders such as Huntington’s disease."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC534915/

Put in a few words... it is important to have the receptor unblocked for many physiological processes. It's a measure you have to work out yourself (with your physician), depending on how aggressive your HPPD is. I worry it will take longer to heal, though, perhaps hinder a full recovery. As argued in this thread, NMDAR's might be required for emotional processing; damage caused by psychedelics which overwhelm the emotional system, serotonergically. There are lots of other methods to try first.

This is (reasoned) speculation, though i.e I haven't conducted my own scientific experiments  :P  (only personal ones - which were successful / not negative )

The point I have personally arrived to with regards to NMDA antagonism.. I take 500mg magnesium l-threonate (nmda antagonist, which crosses the blood-brain barrier more readily than other forms of magnesium and with said nootropic effects) before I go to sleep. This is because I see it as a 'switch off', allowing for a neuroprotective and deeper sleep. It is also said, due to it's NMDA antagonism, to upregulate NMDA receptors. I wouldn't take it in the day, where my eyes will be open and new experiences with the ability to form new synaptic pathways might be hindered. I doubt I would ever take an NMDA antagonist other than a form of magnesium.

Our findings suggest that an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions.

http://www.ncbi.nlm.nih.gov/pubmed/20152124

My conclusion is that NMDA modulation (think regulation)is a useful therapeutic target.

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Upon further investigation, I found that GLYX-13 actually acts as an agonist at hypofunctional NMDARs, yet as an antagonist at NMDARs with higher activity. This is as close as I can imagine to NMDA modulation. I should have it next week, upon trial thereof I will open a new thread to log my experience.

 

GLYX-13 activates the NMDAR at comparatively low levels of NMDAR activity, but acts as an antagonist at higher levels of NMDAR activity.

GLYX-13, a NMDAR glycine site functional partial agonist, induces antidepressant-like effects without Ketamine-like side-effects.

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Upon further investigation, I found that GLYX-13 actually acts as an agonist at hypofunctional NMDARs, yet as an antagonist at NMDARs with higher activity. This is as close as I can imagine to NMDA modulation. I should have it next week, upon trial thereof I will open a new thread to log my experience.

 

GLYX-13, a NMDAR glycine site functional partial agonist, induces antidepressant-like effects without Ketamine-like side-effects.

Yes, this action seems relevant to me !

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NMDA agonists and antagonists both upregulate NMDA receptors.

http://www.jneurosci.org/content/16/7/2172.full.pdf
http://www.ncbi.nlm.nih.gov/pubmed/20007519
http://www.ncbi.nlm.nih.gov/pubmed/20152124


Hm.

So, on the one hand NMDA antagonists upregulate the receptor they bind to, on the other, they block it.. a receptor important for learning and memory. What are we to do? I guess this is why modulators are the best shout.. or compounds they have both agonist and antagonist qualities.

Magnesium L-threonate is one of the most interesting compounds I have come across - and I have had success taking up to 2g without any laxative effects. I only notice a small effect from it, but theoretically it looks like a great supp for HPPD.

 

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NMDA agonists and antagonists both upregulate NMDA receptors.

Is that sort of thing unique to NMDAR's? I've never heard about agonists upregulating receptors - but then again, I'm not well-versed in neurobiology :)

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Is that sort of thing unique to NMDAR's? I've never heard about agonists upregulating receptors - but then again, I'm not well-versed in neurobiology :)

I'm not quite sure. I don't recall reading anything about agonists upregulating receptors either..! Neither am I :P  

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Here's a copy-paste of something I was gonna post in Missjess' thread, before I realized it didn't belong there:

Currently I'm trying to develop an approach to effectively, yet safely agonize the NMDARs, which could - in theory - aid DP and subsequent body distortions. Not sure what the implications for visuals would be though. I've narrowed it down to activating the synaptic NR2A subunit of the NMDAR, which should be without excitotoxic effect. However no ligands currently exist to do this, so the best I've come up with so far is a combination of D-serine and an extrasynaptic NMDA antagonist (e.g. Nitromemantine) in an attempt to funnel D-serine to the NR2A (which is preferably selective to D-serine). All that remains is to cross-reference literature on classic NMDA antagonist dissociatives, and see whether there is a subunit specificity through which their dissociative effect is mediated. So far, however, it seems controversial with conflicting evidence, and as always it's just a guesstimate.

Any input anyone?
 

Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways.

Opposing roles of synaptic and extrasynaptic NMDA receptors in neuronal calcium signalling and BDNF gene regulation.

Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists

Synaptic versus extrasynaptic NMDA receptors: Role in PCP-induced neurotoxicity and development of locomotor sensitization

Excitotoxicity in vitro by NR2A- and NR2B-containing NMDA receptors

DIFFERENTIAL ROLE OF NR2A AND NR2B NMDA RECEPTORS IN MEDIATING PHENCYCLIDINE-INDUCED PERINATAL NEURONAL APOPTOSIS AND BEHAVIORAL DEFICITS

Substitution for PCP, disruption of prepulse inhibition and hyperactivity induced by N-methyl-D-aspartate receptor antagonists: preferential involvement of the NR2B rather than NR2A subunit

NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both In Vitro and In Vivo

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I'll have to check my sources/notes, but I believe MgT heavily influences NR2B receptors. If so, this can maybe play a large role in my personal HPPD which I believe was heavily influenced by PCP/embalming fluid and DXM. I'm going to give these studies a read through soon. I'd be interested in hearing your more thorough thoughts on the above studies and their relevance to us. Thanks! 

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Hey BPC! That would be nice to have some info on that :) Hmm I haven't really looked too much further in to it yet, though I have found that Naurex (should've known haha) is developing subtype specific ligands; NR1/NR2-A/B/C/D. However, lead selection won't occur until the end of Q2 this year, and Phase 1 is planned to start late 2015.. And seeing as they tend to be delayed, and apparently also secretive, I wouldn't count on any of the info being available any time soon. In any case, it does seem that NR2B antagonism seems more viable for the immediate future than NR2A agonism.

Anyhow.. really hope I can continue my GLYX trials in the next few days; it should be most interesting to see what my experience is at a full dose.
Even if it doesn't work, I've recently come to realize (thanks to somebody pointing out the obvious that I had somehow missed) that partial agonists are competitive antagonists under circumstances when there is a full agonist present. Thus, if it doesn't work, then perhaps the NMDARs were not sufficiently activated because of this. This is why I now have D-Aspartate, which I'll try after GLYX. I'll also order some D-serine; D-serine + D-Aspartate should be more or less the most potent NMDAR activation currently available. I've been trying to find out about how significant the excitotoxicity concerns are with the latter. People have taken the combination before without ill effects though; so perhaps I will do just that without too much fretting over potential excitotoxicity. Or, alternatively, co-administrate Cerebrolysin to mitigate some of it.

Also, it seems from what I've read that D-serine is considered subjectively superior to Sarcosine/Glycine.

Some more links:
The regulatory role of long-term depression in juvenile and adult mouse ocular dominance plasticity

D-Serine Augments NMDA-NR2B Receptor-Dependent  Hippocampal Long-Term Depression and Spatial Reversal  Learning

D-aspartate prevents corticostriatal long-term depression and attenuates schizophrenia-like symptoms induced by amphetamine and MK-801

D-aspartate: an atypical amino acid with neuromodulatory activity in mammals.

New insights on the role of free D-aspartate in the mammalian brain.

 

An interesting blog; a collection of data, contrasting NMDA antagonism against KOR agonism, stating that NMDA antagonists are actually a better model for DP than they are for psychosis:

Salvinorin A as the most complete mimetic of schizophrenia

Longecity:

"Healing the mind from DXM induced psychosis"

"New Nootropic D-serine" (with experiences and combo's)

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Awesome man! You're doing some serious digging. If it wasn't for some of these classes I'd be more apt to look up my specific particular issues, which I've come to grow more familiar with (i.e. the whole idea of damaged/hypofunctional NMDARs and perhaps, low acetylcholine).

 

I believe one of those longecity threads you posted (though perhaps it was another one), a person was going to add pregnenolone to the stack your considering (it plays some role with NMDAr modulation). I'd definitely look into that - it's extremely cheap and you can get pure, bulk powders really easily. Also, I know people taking 1g/day for prolonged periods of time, and Dr. Peat took 3g/day for an entire year. Larger doses may be warranted for people in our position.

 

I'm definitely going to look into ALL of these studies soon, and give my input, along with my previous studies on PCP and DXM induced damage, too. I think we can compile something nice. You should read what I posted from this private peptide forum about cerebrolysin and the most efficacious way to use it (i.e. training your brain via enriching experiences and/or new skills to actually facilitate the neural growth that cerebrolysin induces, but does not ensure; also it increases GLUT1 in the brain, so eat dem carbs ;)) I've also seen doses up to like 60mL/day used, and people in studies who were previously non-responders actually responded to these really large doses.

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Sorry guys, I can't be of much help for a while. Last couple of months of uni, got to put my research on hold. Am starting a Biomedical course later this year though so will be able to get fully on the research :) . Wishing you well, in case you don't hear from me much for a while (I'll still check the boards everyday though)

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@BPC: Thanks. Pregnenolone is quite interesting; I might give it another shot one of these days. 3 grams per day sounds a bit extreme though; generally speaking 50mg is already considered a high dose from what I've read. Yes indeed; neurogenesis probably exerts its best effect when learning/experiencing new things, however I think that that in and of itself should suffice to mediate at least some noticeable change, if sufficiently active. 60ml/day Cerebrolysin would be inconveniently large and expensive.. I think 7,8-DHF may be better in that case. Which studies on DXM and PCP are you referring to? I would very much like to read them, too see if there are any similarities in MoA that may be able to specify the exact mechanism/subtype that causes NMDAR-related dissociation.

@Syntheso: No problem, you've helped enough by starting this thread; it has been quite inspiring! :) Best of luck with uni; that biomedical course sounds like it could come in handy.

I found one interesting news article:

 

Scientists have discovered that by deactivating a major switch in the brain that is linked to learning and memory, memories become jumbled, like "hitting random notes on a keyboard," and lose their sense of association.

"You see a face and think of a name, you see your office, and you think you need to work; everything is associative," says Dr. Joe Tsien, neuroscientist at the Medical College of Georgia at Georgia Regents University. "But in mice lacking an NMDA receptor, you can tell the memory patterns are dull and dissociated."

This revealed that normal mice had brain activity that played "dynamic rhythm," while mice with a faulty NMDA receptor had brain activity that played "random noise."
Dr. Tsien says that the mice with a faulty receptor form the initial patterns of association but do not remember them. He explains that "their tones are flat, the association is poor, while everything we register in the healthy brain is associative."

Original study

 

Also something interesting to note:
 

 

"Lamotrigine attenuation of ketamine-induced effects in humans
In addition to metabotropic glutamate receptor agonists and glycine, glutamate release can be decreased by lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine), an anticonvulsant that stabilises neuronal membranes and attenuates cortical glutamate release via inhibition of use-dependent Na+ channels and P- and N-type calcium channels, and via its effects on K+ channels. Anand et al (2000) have recently shown that lamotrigine reduces the neuropsychiatric effects induced in healthy humans by sub-anaesthetic doses of ketamine. However, further studies are needed because lamotrigine affects other neurotransmitter systems (e.g., 5-HT, GABA and dopamine) and it is unclear whether these effects are direct or secondary to the effects on glutamate release."

Source
Nevermind the Lamotrigine; the glycine is what interests me here. This may explain the lack of efficacy I've experienced with glycine, even at high doses. Then again, I haven't been able to find whether this is regarding long-term use or short term, as the inhibition of glutamate release may simply be an adaptive homeostatic response.

Anyhow.. will attempt to look further in to this some time this week. Having some troubles with cognition lately due to sudden unilateral deafness. Going to see a doc tomorrow, so hopefully if and when it's resolved, I can resume investigation in to this at a better pace.

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@BPC: Thanks. Pregnenolone is quite interesting; I might give it another shot one of these days. 3 grams per day sounds a bit extreme though; generally speaking 50mg is already considered a high dose from what I've read. Yes indeed; neurogenesis probably exerts its best effect when learning/experiencing new things, however I think that that in and of itself should suffice to mediate at least some noticeable change, if sufficiently active. 60ml/day Cerebrolysin would be inconveniently large and expensive.. I think 7,8-DHF may be better in that case. Which studies on DXM and PCP are you referring to? I would very much like to read them, too see if there are any similarities in MoA that may be able to specify the exact mechanism/subtype that causes NMDAR-related dissociation.

Anyhow.. will attempt to look further in to this some time this week. Having some troubles with cognition lately due to sudden unilateral deafness. Going to see a doc tomorrow, so hopefully if and when it's resolved, I can resume investigation in to this at a better pace.

 

Yeah, pregnenolone is a very interesting substance. For awhile I did a blinded experiment with the help of my mom, and every time I was administered preg. my working memory, cued attention, and reaction times all increased, along with a very noticeable increase in mood. In fact, I felt as though I smoked weed, haha. I have some left and will be taking about 70mg/day until I run out. You are correct: 1-3g/day is quite a lot, especially over prolonged periods of time (such as a year).  Dr. Ray Sahelian recommends never exceeding 1-5mg/day, yet Dr. Peat maintains that many grams a day is entirely safe. I have been reading Hans Selye's endocrinology books/texts, and I'd have to say that it does seem that as long as you support your preg. supplementation with adequate carbs, total calories, and some other things, it should be used appropriately (by your body) and not mess with other hormones like estradiol and DHT. 

 

You should also look into Progesterone and DHEA, if you haven't already. I posted like 5-10 studies in the HPPD stack thread recently about how amazing progesterone looks for brain regeneration and maintenance; it plays a large role in myelination AND actually modulates GABAa subtype receptors. Interestingly, Dr. Peat considers all 3, preg, prog, and DHEA 'youth associated hormones'.

 

I'll look for the studies on PCP and DXM again; I probably have them in my EverNote cloud somewhere (I have wayyyy too many 'notes' and links in that cloud, haha). They can be found on Erowid, though. You are correct again, in that 60ml/day of Cere would be quite expensive. Are you going to be acquiring/using 7,8-DHF? I wanted to get Dihexa, but was adamant on purchasing NSI, and now I think I'm going to cancel that order. I think, based off of my preliminary research on Cere, I/you'd be able to do a 'loading dose' of 60ml/day of Cere followed by 5-10ml/day from there on out; still expensive, yet less so than 60ml/day for weeks-months. After Coluracetam with my increasingly frequent/intense z-health practice, along with about 5-7 NeurOptimal sessions I'll be doing this month, I'll definitely be trying Cere and posting back. 

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Ughh, I'm looking up studies on the PCP-NMDA/glutamatergic relationship and it's giving me some PTSD-like responses; I've been feeling rather well today (not HPPD-free, haha, but just better than I typically do), and right away after reading some abstracts I got extremely anxious and almost flashback-like responses. I was intrigued after I saw Coluracetam antagonized PCP induced cognitive dysfunction. Unfortunately I don't have access to the full-text at the moment, so to what degree it achieved this and with what concentration in the plasma/serum.. I don't know. It's given me further hope for Colu. to help me a bit, so I think I'm about to order some.

 

Interestingly and frighteningly, from the abstracts I just read, if DXM/PCP/embalming fluid are behind my HPPD/associated problems, the foundation of my problems are probably much more extensive than I had every imagined. PCP alone induces epigenetic changes in the brain, decreases NO synthesis, decreases 5-HT2A receptor density, dopamine turnover, and changes "septal ChAT-positive cells"; it may also negatively impact GABAa receptors and increase "ventrostriatal dynorphin A expression." I can't tell from the first abstract if dopamine turnover means that I'd have increased or decreased total levels of dopamine; I feel as though I don't have dopamine problems as I don't typically have motivation problems and have a lot of mental energy; though I do have some ADD/ADHD like tendencies since this whole HPPD fiasco - I often have dozens of tabs open at once, going through each of them and bouncing back and forth, along with starting something (say, a blog), only to then open facebook, gmail, and youtube, then open some clinical studies, get back to the blog, etc. But correct me if I'm wrong, it looks like I may have severely decreased NMDAr's/damaged glutamatergic system functioning; decreased acetylcholine; decreased 5-HT2A receptor density; messed up GABAa subtype receptors; and lastly, increased dynorphin A expression. Eeeek! 

 

I'll take a few minutes to look into DXM, now, because the other studies are gettin' to me  :wacko: 

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every time I was administered preg. my working memory, cued attention, and reaction times all increased, along with a very noticeable increase in mood. In fact, I felt as though I smoked weed, haha.

Wait, weed gives you increased working memory, attention span and reaction times?
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But correct me if I'm wrong, it looks like I may have severely decreased NMDAr's/damaged glutamatergic system functioning; decreased acetylcholine; decreased 5-HT2A receptor density; messed up GABAa subtype receptors; and lastly, increased dynorphin A expression. Eeeek!

Well, fortunately most of those can be mitigated. Several ligands could mitigate NMDAR loss, LMM for the ChAT decrease IIRC, stress alone would mitigate 5HT2A receptor density loss, perhaps Kava Kava for GABA-A upregulation, and well.. Dynorphic expression is increased with almost any recreational substance (ab)use.

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Wait, weed gives you increased working memory, attention span and reaction times?

No, haha, though I can potentially see some of those benefits with certain stains... although I may never have the ability to smoke weed again  :unsure:

 

Pregnenolone gave me these benefits. I can look in my journal for the exact 'scores' I had on each test, but pregnenolone administration had beneficial acute effects when testing these aspects of cognition, and I'm sure if I stuck with it I could get some benefits. I'm going to have to finish out the rest I have and dose daily, I just never get to it, and my realllyyy disrupted sleep schedule doesn't help.

 

 

Well, fortunately most of those can be mitigated. Several ligands could mitigate NMDAR loss, LMM for the ChAT decrease IIRC, stress alone would mitigate 5HT2A receptor density loss, perhaps Kava Kava for GABA-A upregulation, and well.. Dynorphic expression is increased with almost any recreational substance (ab)use.

That's good to note - thanks for the links! As I thought earlier, MgT does increase/up-regulate NR2B-containing NMDAr's. 

 

"Chronic MgT treatment upregulated NR2B-containing NMDAR and increased activation/expression of downstream signaling molecules in the hippocampus (Figure 4). This was associated with a dramatic increase in short-term synaptic facilitation and long-term potentiation that are critical for learning and memory (Figure 5)."

(...)

"Increase inNR2B-containing NMDAR via overexpression (Tang et al., 1999), augmentation of its membrane transportation (Wong et al., 2002), or reduction of its degradation (Hawasli et al., 2007) leads to enhancement of synaptic plasticity and learning and memory (for review, see Lee and Silva, 2009). In this study, we show that NR2B-containing NMDAR can be upregulated by increase in [Mg2+]o in vitro and elevating brain Mg2+ in vivo."

 

The key word, though, is chronic. Not the green chronic, either, but chronic as in daily/often/over a long period  :P. This may be another therapeutic modality. Question: If one were to use MgT, would it be wise to stop using other forms of magensium outside of dietary sources?

 

I'm starting Coluracetam in the next day or two; now, if only I could find a pure, bulk source of MgT...

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Oxiracetam seems like a viable means to modulating glutamatergic and cholinergic functioning; I can see why ScienceGuy found great success with Ox+Coluracetam:

 

"In animal models, oxiracetam has protected against scopolamine-induced amnesia[32][23][21][33] and amnesia induced by NMDA antagonists including MK-801,[24] AP-7,[34] and AP-5[35] while in vitro glutamate (NMDA) antagonism by kynurenic acid is also inhibited.[36] These anti-amnesiac effects occur in the 3-30mg/kg dosage range (intraperitoneal injections) and the higher dosages tend to abolish amnesia (no significant differences between the toxin with oxiracetam and control). Anti-amnesiac effects occur in both naive and well-trained mice.[24]"

(...)

"These protective effects are similar to Aniracetam and are near absolute against scopolamine, yet require a lower dosage as the rat studies use 3-30mg/kg of oxiracetam as intraperitoneal injections."

(...)

The increased signalling efficiancy in hippocampal cells[9] is thought to be related to an increased release of glutamate and D-Aspartic Acid from hippocampal cells when activated[5] at a concentration of 0.01-5µM without affecting outflow of glutamate or D-AA when the neurons were not activated,[11] although 100µM causes a slight increase. (...) As mentioned in the memory section, oxiracetam at 3-30mg/kg injections into mice prevents amnesia induced by glutaminergic antagonists MK-801,[24] AP-7,[34] and AP-5.[35] In vitro, the suppression of noradrenaline release caused by NDMA antagonists is prevented with oxiracetam at 1μM (with similar potency to Aniracetam).[45]"

(...) 

"Oxiracetam has been noted to prevent the reduction in acetylcholine concentrations induced by electroshock therapy in rats, which was accompanied by preventing amnesia.[46] Since phygostigmine (an acetylcholinesterase inhibitor like Huperzine-A) is known to prevent amnesia secondary to preserving acetylcholine concentrations[47] it is hypothesized that the anti-amnesia properties of oxiracetam against cholinergic antagonists like scopolamine[23][21][33] are due to preserving acetylcholine concentrations, which has been noted against scopolamine-induced amnesia as well with oxiracetam at 50-100mg/kg (partial preservation in the cortex and hippocampus but not striatum).[14] Aniracetam was noted to be slightly more protective in the hippocampus, but inactive in the cortex.[14]

That being said, this is unlikely to solely explain the antiamnesiac effects since depletion of catecholamines (despite preservation of acetylcholine) abolishes the protective effects of oxiracetam against scopolamine.[48]

 The decline in acetylcholine concentrations seen with cholinergic antagonists or amnesiac stressors appears to be prevented to a large degree with oxiracetam, which is thought to play a role in the anti-amnesiac properties (but is likely not the only explanantory factor)

In rats not given anti-cholinergics, both oxiracetam and aniracetam (100mg/kg) fail to significantly modify acetylcholine or choline concentrations in any tested brain region.[14]

Independent of increasing acetylcholine concentrations, oxiracetam appears to increase acetylcholine utilization in the cortex and hippocampus at 100-300mg/kg injections.[49] Repeated daily doses of oxiracetam was noted to increase acetylcholine utilization by 31% relative to control, and appears to be more potent and prolonged than Piracetam.[49]

Furthermore, despite no apparent changes in basal acetylcholine levels in vivo a concentration of 0.1-1µM oxiracetam in hippocampal slices appears to augment acetylcholine release.[11] Basal outflow of acetylcholine from these neurons when not activated was not modified.[11] It is thought that this enhanced release explains the increase in acetylcholine uptake noted with oxiracetam inherently[49][50] which causes a relative depletion of intracellular acetylcholine levels when choline uptake is blocked[49] (which can be explained by increased release rates)."

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 while in vitro glutamate (NMDA) antagonism by kynurenic acid is also inhibited

^This is the most interesting part, I find. Anti-amnesic effect can happen in various ways; the substance needn't necessarily work on the same system I'd think. But that it inhibits KYNA antagonism is highly interesting. Though I wonder whether it inhibits biosynthesis, release, or binding. Nonetheless, very nice find BPC. I will check to see what schizophrenics think of Oxiracetam; several studies indicate the possibility of too much KYNA mucking around with their NMDARs, so it should help them as well.

Re: MgT upregulating NR2B; from what I've found, this is what you don't want happening. NR2A is the one you want to upregulate.. But again; still have to look further in to it, but this is how it seems to me now.

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Re: MgT upregulating NR2B; from what I've found, this is what you don't want happening. NR2A is the one you want to upregulate.. But again; still have to look further in to it, but this is how it seems to me now.

Could you explain why?

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Could you explain why?

Well, as I said I'm not 100% certain, but read through this:

 

Here, we report that in mature cortical cultures, activation of either synaptic or extrasynaptic NR2B-containing NMDA receptors results in excitotoxicity, increasing neuronal apoptosis. In contrast, activation of either synaptic or extrasynaptic NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action against both NMDA receptor-mediated and non-NMDA receptor-mediated neuronal damage.

 

I also just did a write up on "Why not to use the CILTEP stack". I also just noticed this:

 

Here we report that synaptic and extrasynaptic NMDA (N-methyl-D-aspartate) receptors have opposite effects on CREB (cAMP response element binding protein) function, gene regulation and neuron survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have anti-apoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death.

source

 

This indicates that synaptic NMDAR activation increases BDNF expression (good), but also induces CREB activity (see my write-up on why this is unfavorable). Extrasynaptic NMDAR activation causes CREB deactivation which in turn blocks induction of BDNF expression. This, I believe, brings us in a bit of a conundrum where activating synaptic NMDARs would upregulate Dynorphin expression via CREB, thus leading to dissociative symptoms, whereas activating extrasynaptic NMDARs induces the unfavorable blockage of BDNF expression.

Solution? Hmm.. TrkB agonism to compensate for extrasynaptic NMDAR activation induced blockage of BDNF expression?

However yet again there are conflicting statements; the underlined text indicates a difference in synaptic or extrasynaptic NMDAR activation and the effect on apoptosis, whereas the first quote states that there is not in the case of NR2A.

I don't know, I haven't been as meticulous about it as I would like, so perhaps I've made some mistakes/too much assumptions. For example; I'm assuming NR1/NR2A = NR2A, but that may be a receptor coupling of NR1+NR2A that's being referred to, so please take this all with a grain of salt :) All this conflicting stuff is confusing me, so I'm procrastinating, haha!

 

 

NMDA receptor function: subunit composition versus spatial distribution. might be enlightening.

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