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      Hey guys,
       
      I have a question. I'm new to the site, but I've had HPPD for about 3 years now. I also have PTSD (along with several other irrelevant mental disorders).... I'm doing Independent Research on HPPD for a course at my college and I noticed a pattern...
       
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Syntheso

Why NMDA antagonism?

75 posts in this topic

Hear me out. There's lots of emphasis on here placed on NMDA antagonism. As far as I can tell the thinking goes MDMA, LSD -> NMDA agonism -> HPPD (help) --> how to fix --> NMDA antagonism (opposites). This makes sense and I know a lot of people have had success with antagonising the NMDA receptor in mitigating their symptoms. A good example of success with this thinking here.


And here, we see Dextrorphan (an NMDA antagonist) prevents the neurotoxic effects of MDMA in rats. But this is administered with the MDMA. Of course, we don't have this luxury.

But, what about NDMA agonism or selective NDMA agonism?

Check out the profile of GLYX-13:

GLYX-13
- partial NDMA agonist
- enhances memory and learning
- readily crosses the blood brain barrier
- shown to increase Schaffer collateral-CA1 LTP in vitro
- shown toelevate gene expression of hippocampalNR1, a subunit of the NMDA receptor, in 3-month-old rats
- Neuroprotective effects have also been demonstrated in Mongolian Gerbils by delaying the death of CA1, CA3, and dentate gyrus pyramidal neurons under glucose and oxygen-deprived conditions
- 'long lasting antidepressant'

Comments from person here:
 

Quote

Now on to GLYX-13. This one is really cool for a couple different reasons. One, it binds to the glycine site, which is a new class of NMDAR modulators. Two, it is an agonist/antagonist. This means that it can activate the NMDAR and deactivate it depending on the electrical conditions. The racetams also work in this manner, but at an allosteric site. Aniracetam in particular has very similar effects to GLYX-13, just at the allosteric site instead of the glycine site. The advantages of this are enormous. Not only can it protect the neuron from too much calcium influx, it can increase the efficiency of the calcium influx as well.


Okay, now how I actually got to this compound, and the point I will charter into the lands of sounding like an idiot, but, if only to be better informed then that is okay. I am ready to get schooled (raising hands for ignorance) B)

So my thinking and research generally adopts, like quite a few people I have seen here, a PTSD-esque template for HPPD.

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). So the HPPD mind is in some sort of constant fight-flight response, hence, aroused sympathetic nervous system, the HPA axis is affected, neurotransmitters, hormones all over the place blah blah, hence you feel pretty messed up all the time. But you knew that.
Anyway, so until the fight-flight response loop is resolved, I don't think anything is going to fix all this stuff successfully... so, we need a resolution from the top down, then everything else will hopefully figure itself out, or at least be able to. So I am proposing the amygdala and hippocampus as the core pathological areas that need targeting in treatment.


On that I found out about D-Cycloserine.
- Primarily it is used as an tuberculosis antibiotic.

Otherwise;
-It is also being trialed as an adjuvant to exposure therapy for anxiety disorders (e.g. phobias[2]), depression, obsessive-compulsive disorder and schizophrenia.
- Recent research suggests that D-cycloserine (d-4-amino-3-isoxazolidinone) may be effective in treating chronic pain.[3]
- The side effects are mainly central nervous system (CNS) manifestations, i.e. headache, irritability, depression, psychosis convulsions. Co-administration of pyridoxine can reduce the incidence of some of the CNS side effects (e.g. convulsions).
- These psychotropic responses are related to D-cycloserine's action as a partial agonist of the neuronal NMDA receptor for glutamate and have been examined in implications with sensory-related fear extinction in the amygdala,[2] and extinction of cocaine seeking in the nucleus accumbens.[4]
- D-cycloserine is a partial agonist at the glycine receptor, and has been shown to have cognition-enhancing properties for models of Parkinsons disease in primates.[5


Facilitation of Extinction of Conditioned Fear by D-Cycloserine


In PTSD treatment, as many of you will know, exposure therapy does what it says on the tin; the subject is asked to face up to the traumatic experiences of their past with the goal of eventually being able to accept, emotionally process and then rid themselves of them and the anxiety and fear that comes with their avoidance.

Only problem for us is how do you expose yourself to the ineffability of tripping without taking the same substances that brought us here, and, does that even count as exposure? It's hardly going to replicate that trip, especially with the chemical diversity of compounds bought on the street, and the extremely subjective nature of tripping.

I have suggested the idea of exposure using the same substances as potentially beneficial around on this forum, but haven't founded my claims well, because something else would need to go on at the same time as this exposure (if my thinking works) and I can't figure out what. I have pondered on the idea of teaching your body to release certain chemical responses to overwhelm, for example, a bombardment of the visual cortex from a psychedelic substance- a kind of gene response conditioning. However, there appears to exist no such practice as far as my personal research goes. Besides, that all sounds a bit idealistic, futuristic, or stupid.


Back to D-Cycloserine and exposure. Note some of the abstract from the study above;






Like conditioned fear learning, extinction is dependent on a particular protein (the N-methyl-D- aspartate or NMDA receptor) in a part of the brain called the amygdala. Blockade of this receptor blocks extinction and improving the activity of this receptor with a drug called D-cycloserine speeds up extinction in rats. Because exposure-based psychotherapy for fear disorders in hu- mans resembles extinction in several respects, we investi- gated whether D-cycloserine might facilitate the loss of fear in human patients. Consistent with findings from the animal laboratory, patients receiving D-cycloserine bene- fited more from exposure-based psychotherapy than did placebo-treated controls. Although very preliminary, these data provide initial support for the use of cognitive en- hancers in psychotherapy and demonstrate that preclini- cal studies in rodents can have direct benefits to humans.


We see the same here; D-cycloserine augments exposure therapy.

"Blockade of [the NMDA] receptor blocks extinction"... to my analysis, the persistent visuals are evidence for the brain trying to process emotional trauma - the emotional trauma of tripping - hence the reminiscent visuals. If the brain is trying to extinguish trauma, and the blockade of the receptor blocks extinction, why would you want to block it? And why would you in fact not want to help it with a compound such as D-Cycloserine, which, could potentiate the processing of the emotional data? I mean obviously this idea needs a deeper analysis, but I fail to see why it should fall at the first hurdle.

Notes from http://www.ncbi.nlm.nih.gov/books/NBK2532/ (emphasis in bold)




-
Researchers have provided increasing evidence that the NMDA-receptor systems generally, and glutamate-mediated long-term potentiation (LTP) in particular, may play a crucial role in the processes of learning and memory formation. NMDA receptors in the brain have been implicated and been shown to play a crucial role in various types of learning. These receptors have been demonstrated to be involved in Pavlovian fear conditioning (Xu et al., 2001), eyeblink conditioning (Thompson and Disterhoft, 1997), spatial learning (Morris et al., 1986; Shimizu et al., 2000; Tsien et al., 1996), working and reference memory (Levin et al., 1998; May-Simera and Levin, 2003), place preference (Swain et al., 2004), passive-avoidance learning (Danysz et al., 1988), olfactory memory (Si et al., 2004; Maleszka et al., 2000), and reversal learning (Harder et al., 1998).




- It has been suggested that the activation of the NMDA receptor is required for long-term potentiation (LTP) in the hippocampus, amygdala, and medial septum (Izquierdo, 1994; Rockstroh et al., 1996; Scatton et al., 1991). This mechanism has been implicated in memory formation; the involvement of the glutamate-receptor system and LTP is strongly linked to new learning and memory in animal models (Lozano et al., 2001; Scheetz and Constantine-Paton, 1994; Tang et al., 1999, 2001; Wong et al., 2002). Both lesion studies and pharmacological manipulations in experimental animals suggest that the NMDA-receptor system may be important in the induction of memory formation, but not for the maintenance of memories (Constantine-Paton, 1994; Izquierdo, 1991; Izquierdo and Medina, 1993; Liang et al., 1993; Quartermain et al., 1994; Rickard et al., 1994). Indeed, it has been shown that NMDA-receptor blockade after learning a task had no effect on memory performance in humans, whereas blockade of receptors before learning resulted in memory impairment (Hadj Tahar et al., 2004; Oye et al., 1992; Rowland et al., 2005). If blocking this receptor afterwards has no effect on memory performance, what would blocking it achieve? We are left with agonising/modulation the receptor as alternatives.

NMDA alone, systemically administered in rats, has been shown to potentiate cognitive functions (Hlinak and Krejci, 2002; Koek et al., 1990). A recent study (Hlinak and Krejci, 2003) investigated whether systemically administered NMDA can prevent amnesia induced by an NMDA antagonist dizocilpine (MK-801). Using a modified elevated plus maze paradigm, it was demonstrated that NMDA administered subcutaneously immediately after the acquisition session protected the mice against amnesia induced by MK-801 given shortly before the retention session.


NMDA Antagonists

Both acute and subchronic administration of NMDA-receptor antagonists have been shown to impair performance on tasks that seem to depend upon hippocampal or amygdaloid functions (Izquierdo and Medina, 1993;Jentsch and Roth, 1999; Morris et al., 1986). These tasks include passive avoidance (Benvenga and Spaulding, 1988; Kesner and Dakis, 1993; Murray and Ridley, 1997; Venero and Sandi, 1997), acquisition of Morris water maze (Heale and Harley, 1990), and delayed alteration (Verma and Moghaddam, 1996).


The noncompetitive, highly specific N-methyl-D-aspartate NMDA-receptor antagonist dizocilpine (MK-801) (E. H. Wong et al., 1986) has been shown to induce dose-dependent impairment of learning and memory (Benvenga and Spaulding, 1988; Butelman, 1990; Carey et al., 1998; de Lima et al., 2005; Hlinak and Krejci, 1998, 2003; May-Simera and Levin, 2003; Murray and Ridley, 1997; Murray et al., 1995; Venero and Sandi, 1997). It has also been shown that MK-801 selectively disrupts reversal learning in rats using serial reversal tack (van der Meulen et al., 2003). Further, several studies have revealed that MK-801 administration impairs different aspects of learning and memory in the elevated plus maze in rodents (Hlinak and Krejci, 1998, 2000, 2002). Recently, the effects of NMDA-receptor blockade on formation of object-recognition memory were examined in rats. It was found that MK-801 impaired both short- and long- term retention of object-recognition memory when given either before or after training. These results suggest that NMDA-receptor activation is necessary for formation of object-recognition memory (de Lima et al., 2005). Amnesic effects of MK-801 in mice have also been reported. MK-801 injected intravenously in mice before a training trial in a passive-avoidance task produced an amnesic effect similar to that produced by the standard amnesic agent scopolamine, yet the potency of MK-801 was 40 times that of scopolamine. Effects of MK-801 on corticosterone facilitation of long-term memory have been examined in chicks. It has been shown that long-term memory formation for a weak passive-avoidance task in day-old chicks is facilitated by corticosterone administration (Venero and Sandi, 1997) and that intracerebral infusion of MK-801 prevents the facilitating effect of corticosterone when MK-801 is given before the training trial. These results support the view that corticosterone facilitates the formation of long-term memory in this particular learning model through the modulation of the NMDA-receptor system in the brain.In addition to memory impairment, MK-801 has been shown to induce changes in motor activity (Ford et al., 1989). Therefore, it is important to know whether the MK-801 effects upon memory are secondary to its effect on motor disturbance. In an attempt to address this important issue, Carey et al. (1998) examined the effects of MK-801 upon retention of habituation to a novel environment and locomotor activity. It was demonstrated that a low dose of 0.1 mg/kg MK-801, which did not affect locomotor activity, severely interfered with retention of the novel environment. This observation suggests dissociation between the effects of MK-801 on memory and locomotor activity.
The eyeblink classical conditioning paradigm is an extensively used measure of associate learning and memory (Woodruff-Pak et al., 2000). The contribution of the NMDA-receptor system in the brain to classical eyeblink conditioning has been investigated pharmacologically in rabbits and mice. It has been shown that MK-801 slows the rate of acquisition during delay conditioning (Thompson and Disterhoft, 1997).
Using eyeblink classical conditioning in mice, Takatsuki et al. (2001) demonstrated the role of NMDA receptors in acquisition of the conditioned response (CR). Further, these researchers have shown that the contribution of these receptors to extinction is much smaller than their contribution to acquisition in mouse eyeblink conditioning. In these studies, it was shown that MK-801 impaired acquisition of the CR during mouse eyeblink conditioning in a task-dependent manner.
Learning impairments induced by glutamate blockade using MK-801 have also been reported in nonhuman primates. Acquisition and reversal learning of visual-discrimination tasks and acquisition of visuospatial discrimination tasks were assessed in marmosets using the Wisconsin General Test Apparatus. It was shown that MK-801 impaired acquisition of visuospatial (conditional) discrimination (Harder et al., 1998). Lesions of the fornix (Harder et al., 1996) or hippocampus (Ridley et al., 1988,1995) have been shown to produce a specific and severe impairment on visuospatial tasks. Thus, it could be suggested that it is the effect of MK-801 on glutamatergic corticohippocampal projections that is responsible for the visuospatial impairment (Harder et al., 1998).
Selective impairment of learning and blockade of LTP by other NMDA-receptor antagonists has been reported. It has been shown that blockade of NMDA sites with the drug AP5 does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of LTP. Interestingly, chronic intracerebroventricular infusion of D,L-AP5 (which blocks LTP in vitro and in vivo) selectively impaired the acquisition of place learning in the Morris water maze, a type of learning that is dependent on normal hippocampal functioning. These results further suggest that the NMDA-receptor system is involved in spatial learning and supports the hypothesis that LTP is involved in some forms of learning (Morris et al., 1986).
Recently, it was also demonstrated that MPEP at a relatively high dose, but not at low dose, impaired working memory and instrumental learning. MPEP administration also caused a transient increase in dopamine release in the prefrontal cortex and nucleus accumbens. MPEP exposure also augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with low (3 mg/kg) MPEP enhanced the detrimental effects of MK-801 on cognition (Homayoun et al., 2004). These results suggest that an mGlu5-receptor antagonist such as MPEP plays a major role in regulating NMDA-receptor-dependent cognitive functions.
To investigate the involvement of the NMDA receptors in different stages of memory consolidation, Tronel and Sara (2003)recently examined the effect of a competitive NMDA-receptor antagonist, 2-amino-5-phosphonovalerate (APV), on odor-reward associative learning in rats. It was shown that the blockade of NMDA receptors by APV injected intracerebroventricularly immediately after training induced a profound and enduring amnesia, but had no effect when the treatment was delayed 2 hours after training. More specifically, it was shown that the blockade of NMDA receptors in the prelimbic region of the frontal cortex, but not into the hippocampus, impaired memory formation of the odor-reward association in rats. These results confirm the role of NMDA receptors in the early stage of consolidation of a simple odor-reward associative memory and underlie the role of the frontal cortex in consolidation of long-term memory (Tronel and Sara, 2003).
There have also been reports of amnesia in passive-avoidance task induced by posttrial administration of APV into the hippocampus or the amygdala (Ferreira et al., 1992; Zanatta et al., 1996). However, in a recent study, Santini et al. (2001)demonstrated that the amnesia observed 24 hours after systemic administration of NMDA antagonist D(-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP) was transient. The authors argue that the so-called rescued memory at 48 hours supports the existence of late waves of NMDA activity promoting memory consolidation.
Pretraining administration of NMDA-receptor antagonists has been shown to produce anterograde amnesia in Pavlovian fear conditioning (Kim et al., 1991; Xu and Davis, 1992), spatial learning (Hauben et al., 1999), and passive avoidance (Danysz et al., 1988). Intercranial administration of NMDA-receptor antagonist AP5, without impairing performance processes, produced anterograde amnesia when given before training in goldfish (Xu et al., 2001).
Phencyclidine (PCP), a noncompetitive NMDA-receptor antagonist, has been shown to produce both positive and negative symptoms of schizophrenia as well as cognitive defects in healthy humans (Javitt and Zukin, 1991; Tamminga, 1998). PCP has been used to further investigate the role of the NMDA-receptor system in learning and memory. The performance of rats and mice (Podhorna and Didriksen, 2005) in the Morris water maze and spatial continuous recognition memory task have all been shown to be impaired following acute PCP exposure. PCP-treated animals maintained the original learned rule, and they were only impaired in abolishing it and establishing a new rule. This suggests that acute PCP administration at doses of 1.0 and 1.5 mg/kg was able to significantly impair complex cognitive tasks without disrupting simple rule-learning parameters (Abdul-Monim et al., 2003). Recently, it was shown that repeated administration of PCP failed to produce enduring memory impairment in an eight-arm radial arm maze in rats or mice (Li et al., 2003).
Haloperidol failed to ameliorate the deficit in reversal task performance induced by PCP. In contrast, the new atypical antipsychotic ziprasidone produced a significant improvement in impairment of the reversal task performance induced by PCP (Abdul-Monim et al., 2003). Consistent with these findings, it has been demonstrated that in a novel objective recognition test, repeated administration of PCP significantly decreased exploratory preference in the retention test session but not in the training test session. PCP-induced deficits were significantly improved by subsequent sub-chronic administration of clozapine but not haloperidol (Hashimoto et al., 2005).



I fail to see how NMDA antagonists are beneficial (compare NMDA (partial) agonists above, 'improves learning', with the opposite of antagonists) , with a direction to full recovery anyway, are they not the opposite? And appropriate activation of the NMDA receptor plays a critical role in learning, memory LTP. Why would you want to block it/not aid it?


It seems to me that antagonists would only skip over the core issue here without dealing with anything fundmental to a full recovery. They might mitigate symptoms due to messing up the learning/memory system in general (damaging it) rather than helping process the emotional information. I am prepared to be corrected as fallacious :)

In the light of NMDA antagonism simulating schizophrenia and causing memory impairments, is this really even a line of treatment to be considered at all? And are the profiles of D-Cycloserine and GLYX-13 which facilitate the opposite, not in fact more helpful, in resolving more fundamental issues, helping process trauma?

There's lots of anecdotal evidence against what I've said, clearly NMDA antagonists have helped many, I wonder how much relief overall their usage brings. I haven't heard of anyone approaching it from a different angle though, either I'm being stupid or it might be worth a shot :)




I would like to go into more detail in this initial post, but it would take me ages. I will update accordingly.

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On genes... Thanks to brendan for this thread.

 

"It specifically mentions hppd as being possibly caused by upregulation of krox 20 and arc genes".

 

 

From http://deoxy.org/wiki/Acid_Genes

 

 

LSD produced a robust fivefold increase in arc expression in the prefrontal cortex, similar to that seen with the hallucinogenic drug 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane.

Arc gene expression was not increased in the hippocampus by LSD and was not detectable in the midbrain region. This region-specific effect is fascinating in light of the high density of 5-HT2A receptors localized on apical dendrites of pyramidal neurons in the prefrontal cortex... These receptors have been proposed to be the principal targets for hallucinogenic drugs... It is tempting to speculate that upregulation of two genes encoding proteins (arc and Krox-20) linked to synaptic plasticity may represent early sequelae in the pathways that lead to some reported long term effects of LSD use such as Hallucinogen Persisting Perception Disorder..., and the apparent effectiveness of LSD in the treatment of disorders such as alcohol addiction.

 

 

On investigating Arc, I have found some things worth noting in relation to my first post;

 

The immediate early gene Arc is associated with behavioral resilience to stress exposure in an animal model of posttraumatic stress disorder.

Abstract

Mechanisms involved in adaptative and maladaptive changes in neural plasticity and synaptic efficacy in various brain areas are pivotal to understanding the physiology of the response to stress and the pathophysiology of posttraumatic stress disorder (PTSD). Activity-regulated cytoskeletal-associated protein (Arc) is an effector immediate early gene (IEG) which has direct effects on intracellular homeostatic functions. Increased expression of Arc has been associated with increased neuronal activity and with consolidation of long-term memory. It may thus play an important role in mediating experience-induced reorganization and/or development of synaptic connections. This study sought to characterize the pattern of expression of mRNA for the Arc gene in selected brain areas of test subjects classified according to their individual pattern of behavioral response to a stressor, correlated with circulating levels of corticosterone (as a physiological marker of stress response). The hippocampal CA1 and CA3 subregions of individuals whose behavior was minimally or partially disrupted in response to predator scent stress demonstrated significantly increased levels of mRNA for Arc, compared to unexposed controls. The group whose behavior was severely disrupted demonstrated no such upregulation. Consistent with the hypothesis that the Arc gene has a promoting effect on neuronal function and/or structural changes, the lack of Arc expression in the behaviorally and physiologically more severely affected individuals raises the possibility that Arc may be associated with resilience and/or recovery after stress exposure.

 

 

- Upregulation of Arc in minimal/partial cases of PTSD and after administration of LSD.

 

- Arc is important to homeostatic functions, consolidating memories etc. Blocking it would be negative.

 

- 'Increased expression of Arc has been associated with increased neuronal activity and with consolidation of long-term memory' - this could explain why an upregulation of Arc in HPPD patients has caused the 'long-term memory' of persistent visuals, although this contradicts the idea I will set out below.

 

- Contrast these two studies;

 

In PTSD study; The hippocampal CA1 and CA3 subregions of individuals whose behavior was minimally or partially disrupted in response to predator scent stress demonstrated significantly increased levels of mRNA for Arc. 

In LSD study.. Arc gene expression was not increased in the hippocampus by LSD and was not detectable in the midbrain region

 

From PTSD study; 'The group whose behavior was severely disrupted demonstrated no such upregulation'

 

- The last quote contradicts the idea above, that HPPD'ers might have an upregulation of Arc contributing to the long-term memory formation of persistent visuals, if we are to draw parallels between HPPD and PTSD, which is my intention. But we could use it to speculate the following:

 

   - In the LSD genes study, the mice who's gene expression is recorded after administration of LSD, we can assume, are not HPPD mice, given the rarity of the onset of HPPD. Thus, these mice could represent your more average user after administration of LSD. What happens when things go wrong? Does this study necessarily serve as a pathogenetic indicator for conditions like HPPD, just because LSD was common in administration? Are their observations of gene expression a necessary prequel to HPPD onset? Or would you see an entirely different gene expression in a brain pre-wired to walk away with HPPD?

 

Well, I don't really know, but if the answer to the latter question was to be 'yes', I speculate the following could be the case, drawing on the conclusion of the PTSD study. 'The group whose behavior was severely disrupted' (the HPPD'ers) 'demonstrated no such upregulation'. In other words, perhaps people with HPPD do not express the Arc gene appropriately (perhaps little or not at all) in response to trauma such as that which causes HPPD. 'The lack of Arc expression in the behaviorally and physiologically more severely affected individuals raises the possibility that Arc may be associated with resilience and/or recovery after stress exposure'. In which case, again, NMDA agonism or modulation might in fact be beneficial to alleviating HPPD symptoms.

 

NB: I read a study a while back that concluded that the Arc gene and NMDA are more-or-less synonymous, I cannot for the life of me find it. When I do after routing through notes, this should hopefully strengthen some of these ideas.

 

Also consider this study in reference to the above;

 

The Importance of Having Arc  - Expression of the immediate-early gene Arc is required for Hippocampus dependent fear conditioning and blocked by NMDA receptor antagonism - (http://www.jneurosci.org/content/31/31/11200.long)

 

Abstract

Long-lasting, experience-dependent changes in synaptic strength are widely thought to underlie the formation of memories. Many forms of learning-related plasticity are likely mediated by NMDA receptor activation and plasticity-related gene expression in brain areas thought to be important for learning and memory, including the hippocampus. Here, we examined the putative role of activity-regulated cytoskeletal-associated protein (Arc), an immediate-early gene (IEG) whose expression is tightly linked to the induction and maintenance of some forms of neuronal plasticity, in hippocampus-dependent and hippocampus-independent forms of learning. The extent to which learning-induced Arc expression may depend on NMDA receptor activation was also assessed. First, we observed an increase in Arc gene and protein products in both dorsal hippocampus (DH) and ventral hippocampus (VH) of male Sprague Dawley rats after hippocampus-dependent trace and contextual fear conditioning, but not after hippocampus-independent delay fear conditioning. Specific knockdown of Arc using antisense oligodeoxynucleotides (ODNs) in DH or VH attenuated the learning-related expression of Arc protein, and resulted in a dramatic impairment in trace and contextual, but not delay, fear conditioning. Finally, pretraining infusions of the NMDA receptor antagonist APV into the DH or VH blocked the learning-induced enhancement of Arc in a regionally selective manner, suggesting that NMDA receptor activation and Arc translation are functionally coupled to support hippocampus-dependent memory for fear conditioning. Collectively these results provide the first evidence suggesting that NMDA receptor-dependent expression of the IEG Arc in both DH and VH likely underlies the consolidation of a variety of forms of hippocampus-dependent learning.

 

 

 I will leave it at this for now, I have quite a bit more to post though.

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Awesome Syntheso! Not really in the meticulous mood at the moment, so I'll look through it later, but I'm looking forward to having a new idea to explore.
Just one thing that pops to mind is 'excitotoxicity', however from an initial glance this wouldn't be a problem with GLYX-13 in particular.. Other NMDA agonists I'm not so sure of.

GLYX-13 however, is ridiculously expensive. Over $100/mg atm I believe, and though I don't remember the exact doses used, that would put daily treatment in the hundreds of dollars at least. Not to be a party-pooper or anything, haha. Wouldn't be surprised if it'll be available somewhere this/next year from nootropic suppliers for far less of that price. Perhaps Ceretropic is busy with it; they seem pretty frontier focused.

Cheers.

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Awesome Syntheso! Not really in the meticulous mood at the moment, so I'll look through it later, but I'm looking forward to having a new idea to explore.

Just one thing that pops to mind is 'excitotoxicity', however from an initial glance this wouldn't be a problem with GLYX-13 in particular.. Other NMDA agonists I'm not so sure of.

GLYX-13 however, is ridiculously expensive. Over $100/mg atm I believe, and though I don't remember the exact doses used, that would put daily treatment in the hundreds of dollars at least. Not to be a party-pooper or anything, haha. Wouldn't be surprised if it'll be available somewhere this/next year from nootropic suppliers for far less of that price. Perhaps Ceretropic is busy with it; they seem pretty frontier focused.

Cheers.

Hey man! 

Indeed, I am not entirely sure as to the safety of this idea yet, it needs a deeper analysis for sure.

Just to be clear, I am not necessarily saying that all NMDA agonists would be appropriate, but the one's mentioned have an interesting profile worth considering. I haven't looked into the others yet.

Yeah it's a shame about the price of GLYX-13. D-cycloserine you can get a gram for £50. Assuming its amygdalal functions can be harnessed through IV (if I remember correctly it wouldn't work orally), I might give it a shot after some more research. I still don't understand how it would affect the amygdala without a direct injection into it though.. that confuses me.

Best,

S

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This could also suggest a lack of Arc expression in HPPD'ers. 
 

 

Deficient experience-dependent plasticity in the visual cortex of Arc null mice

Within the visual cortex a vast assortment of molecules work in concert to sharpen and refine neuronal circuits throughout development. With the advent of genetic mouse models it is now possible to probe the individual contributions of single molecules implicated in this process. The Arc (activity-regulated cytoskeletal associated) gene is an effector immediate early gene that has been suggested to play a critical role in synaptic plasticity. The goal of this thesis is to understand the workings of Arc within the visual cortex. Specifically, we ask how genetic deletion of Arc influences plasticity, and how visual response properties differ between cells types containing, and not containing Arc. To elucidate a role for Arc in visual cortical plasticity we took advantage of knockin mice expressing GFP in place of Arc protein (referred to as KO mice for simplicity). We combined intrinsic signal imaging, visually evoked potentials, and two-photon in vivo calcium imaging to assess plasticity in juvenile and adult wild-type (WT), heterozygote, and KO mice. We find that plasticity is disrupted in the visual cortex of Arc KO mice in the absence of obvious deficits at the level of basal response properties. In addition, this work has revealed that: 1) Arc is necessary for the establishment of normal ocular dominance during development and critical for deprived eye depression in the visual cortex of juvenile animals 2) Loss of Arc impairs AMPA receptor internalization in visual cortex- a necessary requirement for synaptic weakening after lid suture.(cont.) 3) Open eye potentiation fails to occur after extended deprivation in the absence of Arc 4) Arc is required for stimulus response potentiation in juvenile animals. 5) Arc is not required for the synaptic scaling up of response suggesting a specific role in Hebbian plasticity. 6) Single cell analysis within the binocular zone of Arc-GFP homozygotes reveals that the distribution of Arc lacking GFP-positive cells does not display a contralateral-bias as compared to controls, and the majority of Arc-lacking GFP-positive cells receive equal input from each eye, suggesting that Arc is critical for synaptic weakening during development. Together, these experiments illustrate the essential role for Arc in experience-dependent plasticity within the visual system.
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Glutamate and post-traumatic stress disorder: toward a psychobiology of dissociation.

Abstract

Dissociative cognitive and perceptual alterations commonly occur at the time of traumatization and as an enduring feature of post-traumatic stressdisorder (PTSD). After stress exposure, dissociative symptoms are a predictor of the development of PTSD. Recent preclinical data suggest that stress stimulates the cortico-limbic release of glutamate. The glutamate that is released during stress in animal models influences behavior, induces a variety of changes in neural plasticity that may have long-lasting effects on brain function and behavior, and contributes to neural toxicity. Antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor also stimulates transient cortico-limbic glutamate release in animals. Further, some of the effects of NMDA antagonists in animals are blocked by drugs that attenuate glutamate release. Clinical studies suggest that NMDA antagonists may transiently stimulate glutamate release and produce symptoms resembling dissociative states in humans. A recent study suggests that a drug that reduces glutamate release also attenuates the perceptual effects of the NMDA antagonist, ketamine, in humans. Because of the possible contributions of hyperglutamatergic states to the acute and long-lasting consequences of traumatic stress exposure, the therapeutic and neuroprotective potential of drugs that attenuate glutamate release should be explored in traumatized individuals with dissociative symptoms.

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the therapeutic and neuroprotective potential of drugs that attenuate glutamate release should be explored in traumatized individuals with dissociative symptoms.

It's a tough one.. You obviously don't want glutamatergic excitotoxicity, but I wonder whether mitigating the toxicity/its effects is sufficient to alleviate symptoms? It would be more like slowing down the detrimental effects rather than stopping it all together, or so I'd think. Nice work though! Finding what causes this extensive glutamate release may provide for a better way to stop it from occurring altogether in the first place; on a physiological level that is.

Which may lead back to endocrinology.. And there is development in all kind of hormonal drugs. Problem with hormones is that they effect the entire body, and messing with those can lead to a wide array of changes to the body. IIRC corticosteroid receptor blockers (can't remember the exact scientific name alas) have been made/discovered an are being tested. If these would be brain-specific, that might be interesting..

Perhaps I'm taking it at a wrong angle, but I feel there must be something in between the steps that may be more beneficial/specific. Just a hunch though.

GLYX-13 does look awesome, and I'd like to try it, but yeah.. circumstances and all. Perhaps it's worth the dig to see if there are any other substances that produce the same or similar effects, even if indirectly? Also, what else is involved? I don't know why this is popping to mind, but my mind says "Glycine" and/or "Glucose"..  (EDIT: turns out Glycine is indeed involved.. perhaps worth looking into?)Can't connect the dots myself, but usually when stuff pops into my mind like that, even when I don't know how it's related, it turns out it is related anyway. I'm just too lazy to help you out on this one for now, I'm sorry! But like I said; perhaps an idea to try to understand more about glutamate release, from bottom to top and all interlinking mechanisms that play with it, to get a bigger picture.

Again; nice work!

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I'll respond properly tomorrow, but the idea I am trying to work on is chemically induced fear extinction. This wouldn't be able to occur if NMDA receptor was blocked. It is generally believed now that fear extinction does not work by forgetting fear memories, but creating new memories. To do this you need the availability of synaptic plasticity and LTP; unblocked NMDA receptors are required. There are also many other regions that are involved.. my initial focus on the amygdala + hippocampus might have been too narrow, then again, I am still reading things that suggest perhaps not.

Cheers mate. You're right.. actually was part of my reading today.

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I dont know the exact mechanism(s) of action, but after my car accident I was put on tramadol because vicodin made me sick. The tramadol wasnt that great for the pain (herniated discs L3-L5 lumbar) but it had an immense effect on my hppd. First it really helped my anxiety/depression, which made me dwell much less, and eventually i noticed that the less time i dwelled on my plight, the more my visuals dissapated. Ive said before that Im not 100% positive that tramadol was the key to everything, but Obviously it didnt hurt. Anyone else tried tramadol for their hppd symptoms?

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I dont know the exact mechanism(s) of action, but after my car accident I was put on tramadol because vicodin made me sick. The tramadol wasnt that great for the pain (herniated discs L3-L5 lumbar) but it had an immense effect on my hppd. First it really helped my anxiety/depression, which made me dwell much less, and eventually i noticed that the less time i dwelled on my plight, the more my visuals dissapated. Ive said before that Im not 100% positive that tramadol was the key to everything, but Obviously it didnt hurt. Anyone else tried tramadol for their hppd symptoms?

Interesting. It acts on quite a few receptors, NMDA antagonism is indeed one. I wonder exactly what really helped or if the whole combination just happened to work well. Has your HPPD cleared up/what level is it at now?

I might look into this further!

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Sorry, i was doing a line of K when i read this, am I doing something wrong or right? (Irony,

yes, but simplify for the liberal arts guy here.

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Merkan, on 17 Sept 2013 - 15:10, said:

Sorry, i was doing a line of K when i read this, am I doing something wrong or right? (Irony,

yes, but simplify for the liberal arts guy here.

So :P ? I'm a musician..! I don't think what I wrote was particularly complex, it reads like an argument, not really scientific or technical. I'm suggesting that NMDA antagonists are negative in HPPD recovery. Still, bang some K :P .. I actually carried on doing K until a few months back because I inferred that NMDA antagonists were beneficial from what other people had written.. that was before I started digging in myself!

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Syntheso:

My HPPD was really bad. The visuals and anxiety/depression basically made me an agoraphob. Visuals included snow/static/rain, halos, tracers, geometric patterns when eyes closed or in dark place, negative image retention, periphery movement in my vision, and tracers/floaters, etc...

My visuals now...almost non existent. I have to really focus on seeing the visual anomolies just to even vaguely spot them. It is so crazy how far it has come. I wouldve literally cried if this self had told my past self it would be like this. I thought life was over.

As for other things i was doing...my diet sucked. With hppd and bed ridden from herniated discs, you can imagine how much processed food and drinks/soda i put in my belly. Obviously wasjt working out either.

I know tramadol has some wicked mode of action and whatever it does, i think it really did kick start my symptom remission.

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Hah, I'll read over this now. I was just about to post about Nefiracetam, it potentiates NMDA receptors (plus the racetam cognitive stuff) + modulates the glycine site. Have you tried it Odisa?

http://www.ncbi.nlm.nih.gov/pubmed/17095583

Although SG recommends short term usage only; http://www.longecity.org/forum/topic/54506-nefiracetam-another-reason-to-avoid-prolonged-usage/

I will post about some more compounds shortly.


Edit:

More of interest on Nefiracetam.

 

Mechanisms of action of cognitive enhancers on neuroreceptors.

No strategies for curing Alzheimer's disease have been developed yet as we do not know the exact cause of the disease. The only therapy that is available for patients is symptomatic treatment. Since Alzheimer's disease is associated with downregulation of the cholinergic system in the brain, its stimulation is expected to improve the patients' cognition, learning, and memory. Four anticholinesterases have been approved in the U.S.A. for the treatment of Alzheimer's disease patients. However, because of the inhibition of cholinesterases, these drugs have side effects and their effectiveness does not last long. Thus new approaches are needed. One approach is to stimulate directly nicotinic acetylcholine (nACh) receptors in the brain, and another is to stimulate NMDA receptors which are also known to be downregulated in Alzheimer's patients. Nefiracetam has been shown to potentiate ACh currents in the alpha4beta2 receptor of rat cortical neurons with a bell-shaped dose-response relationship and the maximum effect at 1 nM. This effect was exerted via G(s) proteins. The alpha7 receptor was almost unaffected by nefiracetam. Nefiracetam also potentiated NMDA currents with the maximum effect at 10 nM via interaction with the glycine-binding site of the receptor. Galantamine had a moderate potentiating effect on the alpha4beta2 receptor and potentiated NMDA currents with the maximum effect at 1 microM. However, galantamine did not interact with the glycine-binding site. Donepezil, a potent anticholinesterase, also potentiated NMDA currents at 1-10000 nM. In conclusion, these three drugs potentiate the activity not only of the cholinergic system but also of the NMDA system, thereby stimulating the downregulated nACh receptors and NMDA receptors to improve patients' learning, cognition, and memory.
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Syntheso:
My HPPD was really bad. The visuals and anxiety/depression basically made me an agoraphob. Visuals included snow/static/rain, halos, tracers, geometric patterns when eyes closed or in dark place, negative image retention, periphery movement in my vision, and tracers/floaters, etc...
My visuals now...almost non existent. I have to really focus on seeing the visual anomolies just to even vaguely spot them. It is so crazy how far it has come. I wouldve literally cried if this self had told my past self it would be like this. I thought life was over.
As for other things i was doing...my diet sucked. With hppd and bed ridden from herniated discs, you can imagine how much processed food and drinks/soda i put in my belly. Obviously wasjt working out either.
I know tramadol has some wicked mode of action and whatever it does, i think it really did kick start my symptom remission.


Good for you! Glad to hear a success story. How long did you have HPPD before the tramadol intervention?

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TOPIRAMATE has been recommended as an adjunctive treatment of posttraumatic epilepsy and is also indicated for the treatment of migraine headaches, which commonly occur after concussive injury. Although the use of topiramate may be effective in treating seizures, its association with cognitive side effects may limit its use.

MECHANISM OF ACTION

The mechanism of action of topiramate in treating epilepsy is thought to involve (1) potentiating inhibition via the [gamma]-aminobutyric acid (GABA) neurotransmitter system, (2) blocking voltage-dependent sodium channels, (3) modulating high-voltage-activated calcium channels, and (4) glutamate antagonism by blocking non-NMDA receptors.1 Anti-epileptic drugs (AED) are effective because of their ability to reduce neuronal activation, and thus reduce the likelihood of excessive firing that triggers the seizure. However, the mechanism responsible for its efficacy against seizures may also be responsible for the cognitive problems because of reduced neuronal activation. Yet, not all AEDs are equally impairing to cognition, and it likely involves more than the potentiation of the GABAergic system, since gabapentin is thought to act on the GABA system but has relatively few cognitive effects2; similarly, tiagabine, which acts predominantly by inhibiting reuptake of GABA, has fewer cognitive side effects than topiramate.3 The multiple mechanisms of action of topiramate are thought to play a major role in cognition.4

Functional and anatomical correlates may also provide clues to the mechanisms for topiramate's cognitive effects. One study using functional MRI showed a neuroanatomical relationship between decreased activation of the left prefrontal cortex and cognitive language impairment with topiramate therapy in patients with epilepsy.2 Moreover, healthy volunteers who received topiramate showed changes on evoked potentials consistent with disruption of neuronal mechanisms important for maintenance of information in working memory, which may account for topiramate's adverse impact on performance speed and accuracy.5

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Well i first noticed the visuals and "out of body" feeling the day after a 6 gram hydroponic mushroom trip in 2002. I got in the accident in august 2007 (2nd day of law school in an unfamiliar city with no friends family anywhere nearby...which sucked!). Noticed symptom remission about 2 weeks later. Symptom remission continued to current state taking about 2 months all in all. So symptom free (basically) since late october 2007.

Maybe it wasnt really tramadol and just maybe my brain chemistry changed, or maybe the tramadol rearranged my brain chemistry to alleviate hppd symptoms. Not sure. I wish it were a cure for everyone, but ive read alot of people with hppd have problems taking it, some even have symptom exacerbation. I dont understand nuerology at all, so i cant even begim to hypothesize why i got help from it and others are "hurt" by it. Maybe someone who understands brain chemistry better than i could explain...cuz i have no friggin clue.

Good for you! Glad to hear a success story. How long did you have HPPD before the tramadol intervention?

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Well, it worked for you..! One question - how's your memory and general cognitive abilities?

Pretty good. I still remember almost everything during that time, and my memory now is sharp. I did notice focusing and problem solving was difficult during the height of my hppd, but memory never really took a hit. Hope that helps

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Pretty good. I still remember almost everything during that time, and my memory now is sharp. I did notice focusing and problem solving was difficult during the height of my hppd, but memory never really took a hit. Hope that helps

Cool, sorry, one more thing - if you stop taking tramadol.. it all comes flooding back?

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Cool, sorry, one more thing - if you stop taking tramadol.. it all comes flooding back?

No prob. About the tramadol...i dont know, i have only not had the but one time (for 2 days), and the detox was such a mess that i dont think i wouldve noticed. The great thing about tramadol is that the half-life is around 16-20 hours. That makes it pretty hard to clear your bloodstream of tramadol.

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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.

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