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Small update.. 

I am put off by NMDA antagonists, certainly long term, due to the blocking of the NMDAR's, which are required for learning and memory.

My concerns are summarised well here.

Failures and Successes of NMDA Receptor Antagonists: Molecular Basis for the Use of Open-Channel Blockers like Memantine in the Treatment of Acute and Chronic Neurologic Insults

 

ABSTRACT

Summary: Excitotoxicity, defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, has been implicated as one of the key factors contributing to neuronal injury and death in a wide range of both acute and chronic neurologic disorders. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-d-aspartate (NMDA)-type glutamate receptors and hence excessive Ca2+ influx through the receptor’s associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function; potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of diseases including stroke and neurodegenerative disorders such as Huntington’s disease. In contrast, studies in my laboratory were the first to show that memantine, an adamantane derivative, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Past clinical use for other indications has demonstrated that memantine is well tolerated, and it has recently been approved in both Europe and the USA for the treatment of dementia of the Alzheimer’s type. Clinical studies of the safety and efficacy of memantine for other neurological disorders, including glaucoma and other forms of dementia, are currently underway. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than does memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, in addition to its ion channel, that could potentially be used for safe but effective clinical intervention.

I would be interested to hear some case reports from people on the board trying Memantine; another member has made a post about it in this forum. A family relative with Alzheimer's, most notably anxiolytically, has seen a huge improvement since being on Memantine. I would try myself but I am convinced that appropriate NMDA receptor modulation would be more beneficial in the long run.

On a different note, on the mention of glycine.. this is interesting:

Rapid recovery from major depression using magnesium treatment. 

(http://www.ncbi.nlm.nih.gov/pubmed/16542786)

Abstract

Major depression is a mood disorder characterized by a sense of inadequacy, despondency, decreased activity, pessimism, anhedonia and sadness where these symptoms severely disrupt and adversely affect the person's life, sometimes to such an extent that suicide is attempted or results. Antidepressant drugs are not always effective and some have been accused of causing an increased number of suicides particularly in young people. Magnesium deficiency is well known to produce neuropathologies. Only 16% of the magnesium found in whole wheat remains in refined flour, and magnesium has been removed from most drinking water supplies, setting a stage for human magnesium deficiency. Magnesium ions regulate calcium ion flow in neuronal calcium channels, helping to regulate neuronal nitric oxide production. In magnesium deficiency, neuronal requirements for magnesium may not be met, causing neuronal damage which could manifest as depression. Magnesium treatment is hypothesized to be effective in treating major depression resulting from intraneuronal magnesium deficits. These magnesium ion neuronal deficits may be induced by stress hormones, excessive dietary calcium as well as dietary deficiencies of magnesium. Case histories are presented showing rapid recovery (less than 7 days) from major depression using 125-300 mg of magnesium (as glycinate and taurinate) with each meal and at bedtime. Magnesium was found usually effective for treatment of depression in general use. Related and accompanying mental illnesses in these case histories including traumatic brain injury, headache, suicidal ideation, anxiety, irritability, insomnia, postpartum depression, cocaine, alcohol and tobacco abuse, hypersensitivity to calcium, short-term memory loss and IQ loss were also benefited. Dietary deficiencies of magnesium, coupled with excess calcium and stress may cause many cases of other related symptoms including agitation, anxiety, irritability, confusion, asthenia, sleeplessness, headache, delirium, hallucinations and hyperexcitability, with each of these having been previously documented. The possibility that magnesium deficiency is the cause of most major depression and related mental health problems including IQ loss and addiction is enormously important to public health and is recommended for immediate further study. Fortifying refined grain and drinking water with biologically available magnesium to pre-twentieth century levels is recommended.

 

I wonder why they used these forms of magnesium. Can anyone get the full text? Perhaps magnesium glycinate would be a more effective kind for us.

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As posited in an earlier post, a lack of Arc gene expression might explain our persistently experienced HPPD phenomena. These two studies discuss how it is induced.

Arc/Arg3.1 translation is controlled by convergent N-methyl-D-aspartate and Gs-coupled receptor signaling pathways.

Bloomer WA, VanDongen HM, VanDongen AM.

Source

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.

Abstract

Arc/Arg3.1 is an immediate early gene whose expression is necessary for the late-phase of long-term potentiation (LTP) and memory consolidation. Whereas pathways regulating Arc transcription have been extensively investigated, less is known about the role of post-transcriptional mechanisms in Arc expression. Fluorescence microscopy experiments in cultured hippocampal neurons revealed that Arc protein level was dramatically increased by activation of the cAMP-dependent protein kinase (PKA) pathway, which is implicated in long-term memory. A PKA-dependent increase in Arc protein level was observed after pharmacological or synaptic activation of N-methyl-D-aspartate (NMDA) receptors, which play a critical role in both LTP induction and learning. Arc protein was also up-regulated by activation of PKA through G(s)-coupled dopamine and beta-adrenergic receptors, which regulate the late-phase of LTP and memory. When agonists for the NMDA and G(s)-coupled receptors were co-applied, they had an additive effect on Arc protein expression. Interestingly, G(s)-coupled receptor stimulation was ineffective in the presence of an NMDA receptor antagonist, suggesting calcium influx through the NMDA receptor plays a gating role in this pathway. Stimulation of the cAMP/PKA pathway did not affect Arc mRNA level or protein stability, identifying translational efficacy as the main determinant of Arc protein expression level. It is concluded that efficient Arc translation requires NMDA receptor activity, whereas a further enhancement can be achieved with activation of G(s)-coupled receptors. These experiments have, therefore, revealed remarkable similarities in the signaling pathways that control Arc expression and those that regulate LTP, learning, and memory.

Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation.

Waltereit R, Dammermann B, Wulff P, Scafidi J, Staubli U, Kauselmann G, Bundman M, Kuhl D.

Source

Institut fuer Neurale Signalverarbeitung, Zentrum für Molekulare Neurobiologie Hamburg, 20246 Hamburg, Germany.

Abstract

Long-term potentiation (LTP) is a cellular model for persistent synaptic plasticity in the mammalian brain. Like several forms of memory, long-lasting LTP requires cAMP-mediated activation of protein kinase A (PKA) and is dependent on gene transcription. Consequently, activity-dependent genes such as c-fos that contain cAMP response elements (CREs) in their 5' regulatory region have been studied intensely. More recently, arg3.1/arc became of interest, because after synaptic stimulation, arg3.1/arc mRNA is rapidly induced and distributed to dendritic processes and may be locally translated there to facilitate synapse-specific modifications. However, to date nothing is known about the signaling mechanisms involved in the induction of this gene. Here we report that arg3.1/arc is robustly induced with LTP stimulation even at intensities that are not sufficient to activate c-fos expression. Unlike c-fos, the 5' regulatory region of arg3.1/arc does not contain a CRE consensus sequence and arg3.1/arc is unresponsive to cAMP in NIH3T3 and Neuro2a cells. However, in PC12 cells and primary cultures of hippocampal neurons, arg3.1/arc can be induced by cAMP and calcium. This induction requires the activity of PKA and mitogen-activated protein kinase, suggesting a neuron-specific pathway for the activation of arg3.1/arc expression.

Noted from above, the Arc gene can be induced by Ca2+ and the cAMP messenger (+ protein kinase A and mitogen-activated protein kinase).

On cAMP...

Recent research suggests that cAMP affects the function of higher-order thinking in the prefrontal cortex through its regulation of ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN). When cAMP stimulates the HCN, the channels open, closing the brain cell to communication and thus interfering with the function of the prefrontal cortex. This research, especially the cognitive deficits in age-related illnesses and ADHD, is of interest to researchers studying the brain.

See this study. Of interest it notes Guanfacine which I am currently trialing.

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  • 2 weeks later...

I have some more research to throw at this, but for now, anecdotally..

For the last three days I have been taking Nefiracetam orally at doses ranging from 150-400mg TID. I have stopped taking magnesium because that would dampen, if not block its effect on the NMDA receptor that I am interested in. In short; thus far I have been feeling very good.

Nefiracetam is a partial NMDA partial agonist, particularly at the glycine site. It is said to potentiate the NMDA receptor. It also has cholinergic mechanisms and is a GABA-A agonist amongst other actions.

The first time I dosed, at 150mg, shortly after I experienced brain fog to the point I was drifting in and out of consciousness, like absence seizures. I have experienced this before many times with brain fog. This was accompanied by freaky sensations which I cannot quite explain.. it was like having presences around me which would sharply appear and leave my consciousness. It is how I would imagine schizophrenia to feel like, in a very mild way. I had to sleep for a couple of hours to resolve this.

I have experienced this sort of thing before; I think more or less exclusively when very fatigued or having consumed alcohol whilst trying to sleep. It could have been a coincidence that this happened after ingesting Nefiracetam - but I doubt it. It could be due to its GABA action (I say this because I have experienced similarly whilst drinking alcohol). I would like to think, given my theory, that some sort of emotional processing was going on, but perhaps I am being idealistic/biased.

Nonetheless, since this first dose, I have continued dosing TID and not experienced those sensations or any brain fog since. I have been feeling, as I said in short, very good. The mildest head tension; other than that, more or less like a normal, if not a more than normally motivated, person. Visuals seem to have not changed.

One thing that occurs to me; Nefiracetam could be particularly useful a) because of its GABA action, which we know is very useful in HPPD B) simultaneously it is potentiating the NMDA receptor. These two things alongside each other are quite interesting.. maybe it would make things quite a bit worse if there was no GABA action to dampen the effect of glutamate release (which presumably Nefiracetam is doing)?

The main point is that I have been dosing something that agonises the NMDA receptor and have not experienced anything negative except for my induction dose. This indicates potential for my theory, but it is still early days. I will keep updating. I am extremely confident that my experience so far suggests huge potential for d-cyclonserine and glyx-13. I would love to try them but I can't get hold of them. If anyone in London fancies meeting up for a drink, I would be more than happy to give you some of my Nefiracetam so we have another case to trial. That is, if you agree with my idea!

I would also like to personally discourage use of NMDA antagonists... fair enough if they work for you, I can understand why you would take anything that mitigated the awful symptoms we experience, but I am sure there are better ways of overcoming this condition. The more and more I read about the NMDA receptor I just don't seem why on earth you would want to block it. This is just my opinion.

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Awesome man, looking forward to hearing more of this! How would you compare it to any other racetams you've tried? I'm up for giving this a go too.

I have only tried Coluracetam, which as you know I have had very positive results with :) . I have some Piracetam but don't really see a point in using it at the moment, esp. as it takes up to 3 weeks to really set in. Would be interesting to see what you think as you have tried quite a lot!

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Awesome.. Do you think either Colu or Nefi to be superior to the other?
That's like 50-70 grams of Glycine man.. Haha. I was thinking of trying that myself. I'm very interested to see how that pans out, however (presumably you know this already) it would probably be best not to combine with Nefi.

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Awesome.. Do you think either Colu or Nefi to be superior to the other?

That's like 50-70 grams of Glycine man.. Haha. I was thinking of trying that myself. I'm very interested to see how that pans out, however (presumably you know this already) it would probably be best not to combine with Nefi.

To be honest, I have yet to notice a huge difference between the two, although I am pretty sure Colu has the upper hand. It seems to me currently, that just upping acetylcholine is doing wonders, whether Nefi or Colu. I can't say whether or not Nefi's NMDA action is helping me or not, but it's not making me feel bad, which is as much as I can suggest thus far.

I actually fibbed... I ended up trying Nefi and Colu last night (150mg/60mg) - I felt a foggy for a bit, but this was resolved by supping Choline Bitartrate (I realised I hadn't supped any choline since trying Nefi + Colu). I felt pretty decent, and continue to.

Hah yeah I know, a lot of Glycine, for my body weight it gets up to around 45g.. definitely going to have to spread that out.. I'll do what they did in the study, up from 4g/day, probably won't need to get that high before I notice stuff. Yeah I figured that wouldn't be a silly idea, besides should probably cycle off the Nefi soon due to the GABA action, as we discussed! Although, I see potential for lower doses of the two, perhaps working synergistically? Unless I've missed something !

Edit; Glycine trial will have to go on hold for now. My o/d has finally maxed out from ordering brain toys :( well, it's my birthday at the weekend, hopefully I'll get some cash.

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This theory, which I have seen intimated in a few different papers, mainly on schizophrenia, is more or less currently what I think.
 

Excessive activation of NMDA receptors (NR) by endogenous glutamate (Glu) causes excitotoxic neuronal degeneration in acute CNS injury syndromes such as stroke and trauma. It has been suggested that excessive NR activation may also play a role in Alzheimer’s disease (AD). We propose that if excessive NR activation plays a role in AD, it is an indirect role in which excessive NR activation destroys NR, thereby rendering the NR system hypofunctional. According to our hypothesis, when the NR system becomes sufficiently hypofunctional it unleashes a complex excitotoxic process (fueled both by acetylcholine and glutamate) which is a major contributing factor to the widespread pattern of neuronal degeneration in AD. This hypothesis is derived in part from evidence that the NR system may, in fact, be hypofunctional in AD, and that experimental induction of NR hypofunction (NRH) in rat brain (by administration of NR antagonist drugs) triggers a pattern of neuronal degeneration resembling that seen in AD.

So - excessive activation of NMDA receptors from [LSD] use damages the NMDA receptors, and renders the NR system hypofunctional, giving rise to some of our symptoms and/or their ability to be resolved. Thus, to reiterate, stimulating the receptors might be a method to help them recover and mitigate the excitotoxic process.

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Just a comment on Tramadol: I tried it too.. I didn't notice much of an effect besides that I would 'dream' I had convulsions. I say dream because I don't know whether it happened for real. As I would drift off I would semi-awaken and experience what I can't describe other than convulsions. Then again, the stuff I had I ordered online and it may well have been bunk, but I did notice that effect. In any case it did nothing for my HPPD or other symptoms.

Tramadol is working for me somewhat as far as mentality goes, as for sight goes light doesn't blind me so bad but that is about all tramadol is doing for my vision, just filtering out some of that evil sun uv rays. For the first week I felt real speedy and in my case speedy means slow but that wore off after the first week. But since taking it my memory has vanished, either I can't tell you what I did yesterday or I just don't feel like trying to remember what I did yesterday, hard to explain but weather the case is days are running together now. Infact I missed my probation last month and didn't even notice, good thing I got a cool p.o., I went to see her Thursday and locked my keys in my car lol. Best way to take tramadol is 50mg at a time every 45min until you reach like 200-250 mg seems to work better then taking 100 mg or 150 mg at once. But I will probably quit tramadol when this script runs out and yes I am going to wean off it. Works pretty well for add adhd but just attacks to many parts of the brain and I think there are better methods. Also Tramadol and Gabapentin aren't to bad that is what I am doing now, cut back on my valiums from 30 mg each day to 10mg a day just overnight and hell I feel pretty great. 

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I'm being lazy, scatty, and just woke up in the middle of the night, so forgive me for not elaborating, but here:

 

http://www.ncbi.nlm.nih.gov/pubmed/23716622

Oooh interesting, perhaps this is a better approach if there is a lack of NMDAR cells, that is, presumably if excitotoxicity kills NMDAR's as opposed to merely damaging them. Perhaps both upregulation and modulation are required to mitigate symptoms related to the NMDAR's.

Would you (open to all) agree that the negative symptoms of schizophrenia relate to some of the symptoms we experience? NMDA-targeted treatments for schizophrenia, from the reports I have read, generally seem to mitigate these symptoms, which to me sounds promising in mitigating symptoms we experience which are the same/related.

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Yes, or perhaps a combination of both.. Preg for the long-term, Nefi for the short.
I'd agree that Schizophrenia's negative symptoms can apply to a wide variety of mental distress, so it's no surprise that they're similar to HPPD's co-morbid symptoms. I've read one report of Nefiracetam completely reversing positive psychotic symptoms, but that just so happens to be from a guy who ripped me off, so I'm not too trusting of the validity of that report. Also, I was looking into Uridine for upregulating my recently downregulated DA receptors.. I read that NMDA antagonists upregulate DA receptors, so I'm wondering whether NMDA agonism may downregulate DA receptors, though obviously that's a simple train of thought.

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I read that NMDA antagonists upregulate DA receptors, so I'm wondering whether NMDA agonism may downregulate DA receptors, though obviously that's a simple train of thought.

Perhaps that explains people's success with NMDA antagonists, as upregulating DA receptors is something sure to make you feel a lot better with HPPD. I still maintain that blocking/dampening the NMDA receptor is not the best approach. If that is the case, then dopamine upping supps would be required, but I haven't read such yet.

It's a shame we can't get hold of these things.. GLYX-13, D-Cyloserine, PregS.. you can get them from the Bio med companies, but you have to be some sort of organisation.. must find someone who can help in this respect.

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I hadn't seen this was Pregnenolone Sulphate.

From wiki:
Interestingly, unlike pregnenolone, pregnenolone sulfate is a negative allosteric modulator of the GABAA receptor[5] as well as a positive allosteric modulator of the NMDA receptor.[6] In addition, it has been shown to activate the transient receptor potential M3 (TRPM3) ion channel in hepatocytes and pancreatic islets causing calcium entry and subsequent insulin release.[7]

And here's another study: http://www.ncbi.nlm.nih.gov/pubmed/11861317.
And I also suggest this one (pregnenolone administration increases PregS concentrations+ its effects in schizophrenia): http://www.sciencedirect.com/science/article/pii/S030645221100786X.

Maybe supping with pregnenolone alone would suffice to bring about positive change? It's pretty available, like here.

Also, I don't know about D-Cycloserine, but I wouldn't be surprised if GLYX-13 hits the nootropic market this year. Even if you were an organization, GLYX-13 would still cost you about 7-8 grand for a single dose, so probably best to wait until it becomes available to the nootcommunity.
Indeed given the known efficacy of prodopaminergic therapy, that may be what's attributable to the benefits of NMDA antagonists.
I agree that NMDA antagonists are probably best to be avoided (that includes alcohol!).

Perhaps a multi-faceted approach of pro(acetyl)cholinergic, prodopaminergic, proNMDAergic, proGABAergic, and condynorphic, might be interesting?
Though that would obviously be a tad difficult to create such a stack. Just a random thought really.

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Yeah I noticed Pregnenolone was available quite widely, just not in sulphate form. Would be worth a try, perhaps. Maybe you can take something else with it to get a sulphate form.. (my chemistry is terrible so wouldn't know)

That would be a pretty interesting stack. I have thought about tackling from many angles, but thought there must be an easier way. I am sure if you focused on a couple of avenues you could get everything to align to alleviate symptoms sufficiently. As you know, different neurotransmitters modulate each other. Serotonin is a key modulator, with implications in modulating glutamate, GABA and dopamine. See; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430669/#!po=3.57143 (this is super duper important, I was meaning to pick this apart and post but totally forgot - anyway, implications should be easily gathered!). High levels of serotonin = DA deficiency. Think this was discussed in the 5-HTA antagonists thread.. I am still waiting for my Cyproheptadine to test the theory. Just came across this which I should post in that thread; http://www.ncbi.nlm.nih.gov/pubmed/8599393

 

 

FINDINGS:

The serotonin system inhibits dopaminergic function at the level of the origin of the dopamine system in the midbrain as well as at the terminal dopaminergic fields in the forebrain. Serotonergic antagonists release the dopamine system from this inhibition. This disinhibition of the dopamine system in the striatum may alleviate neuroleptic-induced extrapyramidal symptoms, and a similar disinhibition in the prefrontal cortex may ameliorate negative symptoms. However, the benefits of combined serotonergic-dopaminergic blockade may be observed in only a narrow dose range and may be lost with doses that produce suprathreshold dopaminergic blockade.


 

My point is, focusing on one or two things which modulate other systems correctly could/should be enough.

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  • 1 month later...
  • 4 weeks later...
  • 3 weeks later...

Just posting to say that there's a GLYX-13 buy going on.. We've only got 4 people so far, but that's enough to buy.
If you wanna join, visit Longecity or shoot me a PM ('formergenius' @ LC).
We're hoping to finalize before Wednesday, otherwise we have to wait for Chinese New Year to pass. Sorry for the short notice.
It's $250/g excl. shipping and 3rd party analysis; a bit on the expensive side, but I'd thought I'd inform you guys anyway.
There's only 4 grams available; but I'm sure one of the participants wouldn't mind splitting a gram so as to make the purchase cheaper.
It could be that we don't finalize before said deadline, in which case new participants will have until the 6th of February to join.

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I am still on a combo of flupirtine (NMDA antagonist properties) and Keppra which has reduced my worst symptom (pain, which increasingly seems connected to my HPPD) by 70-80%, which has allowed me to continue with my studies. There is no change in any of my other symptoms (except possibly tinnitus, which I rarely notice these days). However, I don't want it to be a long-term solution for a few reasons and so I will explore other options in the summer when my exams are over and I have a break.

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Good to hear from you Ghormeh; hope you're doing good.

Unfortunately, one of the participants backed out last-minute. -sad face- sick of waiting.
So looks like the buy is open to participants until the 6th of February.
With some luck, I'll have it next month somewhere, and hopefully the JDTic sooner to pull me through until then.

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  • 3 weeks later...
Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury?
Abstract

Traumatic brain injury (TBI) increases extracellular levels of the excitatory amino acid glutamate and aspartate, and N-methyl-D aspartate (NMDA)-receptor antagonists protect against experimental TBI. These two findings have led to the prevalent hypothesis that excitatory amino acid efflux is a major contributor to the development of neuronal damage subsequent to traumatic injury. However, as with stroke, the hypothesis that high extracellular glutamate is the key to excitotoxicity in TBI conflicts with important data. For example, the initial increase in extracellular glutamate is cleared within 5 min after moderate TBI, whereas antagonists of glutamate receptors and the so- called presynaptic glutamate release inhibitors remain effective when administered 30 min after insult. In this article, we argue that the current concept of excitotoxicity in TBI, centered on high extracellular glutamate, does not withstand scientific scrutiny. As alternatives to explain the beneficial actions of glutamate antagonists in experimental TBI, we propose abnormalities of glutamatergic neurotransmission, such as deficient Mg2+ block of NMDA-receptor ionophore complexes, and phenomena such as spreading depression, which requires activation of glutamate receptors and is detrimental to neurons in damaged/vulnerable brain regions. Finally, we introduce the notion that beneficial effects of glutamate receptor antagonists in experimental models of neurological disorders do not necessarily imply the occurrence of excitotoxic processes. Indeed, glutamate-receptor blockade may be protective by reducing the energy demand required to counterbalance Na+ influx associated with glutamatergic synaptic transmission. In other words, glutamate receptor antagonists (and blockers of voltage-gated Na+-channels) may help nervous tissue to cope with increased permeability of the cellular membrane to ions and reduced efficacy of Na+ extrusion, and thus prevent the decay of transmembrane ionic concentrations gradients.

 

 

 

 

 

Excitotoxicity in neurological disorders--the glutamate paradox.

Abstract

Beneficial effects of glutamate-receptor antagonists in models of neurological disorders are often used to support the notion that endogenous excitotoxicity (i.e. resulting from extracellular accumulation of endogenous glutamate) is a major contributor to neuronal death associated with these conditions. However, this interpretation conflicts with a number of robust and important experimental evidence. Here, emphasis is placed on two key elements: (i) very high extracellular levels of glutamate must be reached to initiate neuronal death, far above those measured in models of neurological disorders; and (ii) changes in extracellular glutamate as measured by microdialysis are not related to changes in the synaptic cleft, i.e. the compartment where neurotransmitter glutamate interacts with its receptors. It has become clear that the diversity and complexity of glutamate-mediated processes allow for a wide range of potential abnormalities (e.g. loss of selectivity of glutamate-operated ion channels, abnormal modulation of glutamate receptors). In addition, as neuronal death subsequent to ischemia and other insults is likely to result from multifactorial processes that may be inter-related, inhibition of glutamate-mediated synaptic transmission may be neuroprotective by increasing the resistance of neurons to other deleterious mechanisms (e.g. inadequate energy supply) that are not directly related to glutamatergic transmission.

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To simplify my thinking (which I am eternally trying to put more thoroughly into a document), the trip(s) that led us to HPPD were traumatic experiences, analogous to watching someone get blown up in a battlefield; the mind goes into overload, and you're left with damaged hippocampal and amygdalal regions, causing a stuck fight-flight response loop between the hippocampus, amygdala and other limbic regions and your visual cortex (of course there are other areas involved too).

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.

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