39 replies to this topic

[Flex]

Acetyl carnitine is known to enhance mGlu2 epigenetically

[medievil]

NAC, I'd say mglur2,3 agonist.

[Galaxyshock]

Suma root / Brazilian Ginseng / Pfaffia glomerata seems to block mGlu-receptors

 

Our results suggest that inhibition of glutamatergic metabotropic receptors and TNF-α may account for the antinociceptive action reported for the HE in models of chemical pain used in this study.

→ source (external link)

 

I experience healthy wellbeing effect from Suma.

Edited by Galaxyshock, 15 September 2014 - 01:42 AM.

[medievil]

This thread reminds me of extremely interesting research i saw on mglur5 and anxiety.

The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles.
Varty GB1, Grilli M, Forlani A, Fredduzzi S, Grzelak ME, Guthrie DH, Hodgson RA, Lu SX, Nicolussi E, Pond AJ, Parker EM, Hunter JC, Higgins GA, Reggiani A, Bertorelli R.
Author information
Abstract
RATIONALE:
Modulation of metabotropic glutamate receptor (mGluR) subtypes represents a novel approach for the treatment of neurological and psychiatric disorders.
OBJECTIVES:
This study was conducted to investigate the role of the mGluR5 and mGluR1 subtypes in the modulation of pain and anxiety.
METHODS:
The mGluR5 antagonists, 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), and the mGluR1 antagonist, (4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine HCl (LY456236), were tested in models of pain [mouse formalin test, rat spinal nerve ligation (SNL)] and anxiety [Vogel conflict, conditioned lick suppression (CLS)], and their efficacious effects were compared to any associated side effects.
RESULTS:
The systemic administration of MPEP, MTEP, and LY456236 reduced hyperalgesia induced by formalin and mechanical allodynia following SNL. However, only LY456236 completely reversed the allodynia. In the anxiety models, MPEP (3--30 mg/kg), MTEP (3--10 mg/kg), and LY456236 (10--30 mg/kg) produced anxiolytic-like effects similar to the benzodiazepine, chlordiazepoxide (CDP, 6 mg/kg). However, only MPEP and MTEP were able to produce a level of anxiolysis comparable to CDP. In a series of tests examining potential side effects, MPEP and MTEP reduced body temperature and locomotor activity and impaired operant responding for food and rotarod performance at doses of 3--30 and 1--30 mg/kg, respectively. LY456236 reduced operant responding at 30 mg/kg.
CONCLUSION:
Both mGluR5 and mGluR1 antagonists are effective in models of pain and anxiety. However, an mGluR1 antagonist was more efficacious than the two mGluR5 antagonists in the pain models, which, conversely, appeared more efficacious in the anxiety models. These findings support the potential utility of mGluR5 and mGluR1 antagonists for both the treatment of chronic pain and as novel anxiolytics.

I remember a review stating mglur5 antagonism caused the strongest anxiolytic effects in certain ways every noticed in research, ill do some more digging tomorrow.

Acamprosate acts on it.

[Galaxyshock]

 

Suma root / Brazilian Ginseng / Pfaffia glomerata seems to block mGlu-receptors

 

Our results suggest that inhibition of glutamatergic metabotropic receptors and TNF-α may account for the antinociceptive action reported for the HE in models of chemical pain used in this study.

→ source (external link)

 

I experience healthy wellbeing effect from Suma.

 

Thank you so much for the responses! Its been pretty difficult finding natural or at least somewhat attainable compounds that act on mGluRs.  I noticed your article refers to Pfaffia Glomerata, while Wikipedia states that Hebanthe Eriantha is known as Suma or Brazilian Ginseng:

 

http://en.wikipedia....banthe_eriantha

 

any idea why the discrepancy?

 

 

I don't know why so many names are used for it, the wikipedia article lists a bunch of synonyms: 

Gomphrena eriantha (Poir.) Moq.

Gomphrena paniculata(Mart.) Moq.

Hebanthe paniculata Mart.

Iresine erianthos Poir.

Iresine paniculata (Mart.) Spreng.

Iresine tenuis Suess.

Pfaffia eriantha (Poir.) Kuntze

Pfaffia paniculata (Mart.)Kuntze

Xeraea paniculata (Mart.) Kuntze

 

Should be the same herb regardless though.

[Flex]

Suma root / Brazilian Ginseng / Pfaffia glomerata seems to block mGlu-receptors

 

Our results suggest that inhibition of glutamatergic metabotropic receptors and TNF-α may account for the antinociceptive action reported for the HE in models of chemical pain used in this study.

→ source (external link)

 

I experience healthy wellbeing effect from Suma.

 

Wowie, good one.

 

Btw acetylcysteine activates also mGlu1 and in high doses mGlu5

http://www.plosone.o...al.pone.0032503

http://www.longecity...ng/#entry678659

[Galaxyshock]

 

Can you describe any personal cognitive or mental from taking Suma? I'm really interested in this one root. Mostly I have seen it used for workouts and alcohol dependence, but it would be great to get more information about its effects on mood. Also did you use an extract or whole root herb?

 

 

Well the effect is subtle, the sense of wellbeing I mentioned, and a calm energizing feeling and increase in libido. In the beginning of usage even mildly euphoric. Stress is handled better, I kinda feel like I have a protective bubble around me. But it doesn't seem "strongly cns-active" or a nootropic if that's what you're looking for, I bet those pharmaceutical specific mGluR antagonists / NAMs are way stronger. I too have used Suma to boost gym workouts, it has some anabolic benefit as I can increase weights and muscles become fuller. I've used powdered whole root bought in bulk, usually 1-2 teaspoons a day mixed in protein drinks. Good stuff.

 

Also like I mentioned somewhere, it seemed to block Phenibut withdrawals somewhat, but I'm not entirely sure of this as I took other stuff too.

Edited by Galaxyshock, 18 September 2014 - 02:01 PM.

[Galaxyshock]

Possible involvement of group I mGluRs in neuroprotective effect of theanine.

 

We investigated the molecular mechanism underlying the neuroprotective effect of theanine, a green tea component, using primary cultured rat cortical neurons, focusing on group I metabotropic glutamate receptors (mGluRs). Theanine and a group I mGluR agonist, DHPG, inhibited the delayed death of neurons caused by brief exposure to glutamate, and this effect of theanine was abolished by group I mGluR antagonists. Although the administration of glutamate alone decreased the neuronal expression of phospholipase C (PLC)-beta1 and -gamma1, which are linked to group I mGluRs, their expression was equal to the control levels on cotreatment with theanine. Treatment with theanine or DHPG alone for 5-7 days resulted in increased expression of PLC-beta1 and -gamma1, and the action of theanine was completely abolished by group I mGluR antagonists. These findings indicate that group I mGluRs might be involved in neuroprotective effect of theanine by increasing the expression levels of PLC-beta1 and -gamma1.

→ source (external link)

[mait]

Fasoracetam has been speculated to be mGLU 2/3/4//7 receptor PAM:

 

http://www.ncbi.nlm....pubmed/10633154

Edited by mait, 09 October 2014 - 06:44 AM.

[Galaxyshock]

Crosstalk between GABAB and mGlu1a receptors reveals new insight into GPCR signal integration

 

http://www.ncbi.nlm....les/PMC2726695/

[Saffron]

Your on the right track by looking for mGluR1 and 5 Antagonists -- thats one of the best mechanisms of action there is. No one knows this. That mechanism of action is key. 

 

Theanine has no significant effect on anything -- when you see studies on stuff they dont care if its in the hundreds of micromole range and will still pubish. Theanine is garbage its like taking flour or sugar. Theres no difference between taking it and corn starch. 

 

 

[Ark]

L Theanine pronounces the effects of other noots and has a very suddle pleasant feel to it when in the right state of mind and doesn't have many reports of interacting negative with users.

Edited by Ark, 28 December 2014 - 08:02 AM.

[Flex]

Theanine is a mGlu1 agonist

http://www.researchg...ect_of_theanine

 

But please could someone tell me an mGlu2/3 Antagonist ?

I´m dying to find anything, exept research chemicals which requires a group buy...

or that affects it negatively like e.g. through an antidepressant or mood stabilizer... anything..

 

Thats the reason why I´m looking for:

We propose that CB1 receptor activation in the striatum decreases glutamate transporter activity and that
the  resulting  increase  in  synaptic  cleft  glutamate  concentration  causes  the  activation  of  presynaptic  mGluRs,  which  then  decrease
glutamate release.

 

Cannabinoids Decrease Corticostriatal Synaptic Transmission via an Effect on Glutamate Uptake

http://www.jneurosci.../11073.full.pdf

 

I think that the loss of affect through Cannabis consumption is partially caused by this mechanism, i.e. increased feedback mechanism by mGlu2/3 receptors

Edited by Flex, 06 April 2015 - 11:11 PM.

[Metagene]

Try searching here: http://www.guidetopharmacology.org

[airplanepeanuts]

Association of Long-Term Nicotine Abstinence with Normal Metabotropic Glutamate Receptor-5 Binding.

http://www.ncbi.nlm....pubmed/25861697

 

Maybe that's part of nicotine's analgesic action?

[gamesguru]

(-)Epicatechin up-regulates GluR2 in cortical neurons.

mRNA levels of the glutamate receptor subunit GluR2 increased by 60%, measured 18 h after a 15 min exposure to (-)epicatechin at physiologically relevant concentrations

 

GluA2 (GluR2) regulates metabotropic glutamate receptor-dependent long-term depression through N-cadherin-dependent and cofilin-mediated actin reorganization.

 

The GluA2 (GluR2) subunit is critical for the regulation of AMPA receptor properties and synaptic plasticity, but the underlying mechanisms remain unclear. Here, we demonstrate that GluA2 regulates metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) through a previously unknown mechanism involving N-cadherin-dependent and cofilin-mediated actin reorganization. We show that GluA2 is indispensable for mGluR-LTD in the hippocampus, and surprisingly this action of GluA2 is mediated by its extracellular domain interaction with N-cadherin. Accordingly, we show that the function of N-cadherin is regulated by and required for mGluR-LTD. Furthermore, we show that the regulatory effect of GluA2/N-cadherin is mediated through activation of Rho GTPase Rac1 and its downstream actin regulator cofilin, and, importantly, the requirement for GluA2/N-cadherin can be overcome by manipulating cofilin. These results provide compelling evidence that the extracellular domain of GluA2 regulates long-lasting synaptic plasticity through a signaling mechanism that is distinct from those used by the other domains of the receptor subunit.

[Mind_Paralysis]

DId the op Furniture find what he was looking for? The first thing that came to my mind is the previously suggested Fasoracetam.

 

When the thread was first posted, knowledge and use of Faso was still in its infancy in the nootropic community, but these days it's more well-known, and the Mglur-agonism / modulation it exhibits is its primary mode of action.

 

In fact, that's why I where interested in it myself - because of its potential to treat ADHD, among those who have the disorder and metabotropic glutamate receptor mutations.

 

Turns out it wasn't super-efficient in treating my own ADHD-problems, but that may be because I don't have the specific mglur -issues that it targets.

 

But still, give it a try, it might just be what you're after.

[Saffron]

Theanine is a mGlu1 agonist

http://www.researchg...ect_of_theanine

 

At what dosage? like 5 grams at once and for 45 minute duration? Not feasible

 

I notice the new drug Fycompa is Schedule III -- mGluR blockers must be good.

Edited by Saffron, 02 September 2015 - 02:25 AM.

[nootist]

Metabotropic glutamate receptor antagonists

Due to the excitement concerning the mGluR theory of FXS, and regulation by FMRP of proteins implicated in autism, trials of mGluR antagonists are among the most anticipated among new treatments for autism spectrum conditions. In an early open-label trial of fenobam, a mGluR5 antagonist, was tried in 12 individuals with FXS (Berry-Kravis et al. 2009). Fenobam was granted orphan-drug status by the FDA in 2008 to facilitate potential new indications. In this first trial of an mGluR5 agent in FXS, improvements were noted in a laboratory measure of prepulse inhibition of the acoustic startle response in 50 percent of the patients. AFQ056, a negative allosteric modulator of mGluR5 developed by Novartis, has been examined in a single randomized, placebo-controlled study (Jacquemont et al. 2011). No significant effects of the treatment were observed on the primary outcome measure for the study. In a posthoc exploration of the data, however, it was noted that 7 of the 30 patients with a fully methylated FMRI promotor had significant improvements relative to placebo, suggesting that the benefits may be more pronounced in the more severely affected patients. There are several ongoing trials of AFQ056 in FXS (ClinicalTrials.gov: NCT01433354, NCT01348087, NCT01253629, NCT01482143). To date, there are no studies of mGluR5 antagonists in idiopathic autism.

→ source (external link)

[gamesguru]

The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: a comparison of efficacy and side-effect profiles.
Both mGluR5 and mGluR1 antagonists are effective in models of pain and anxiety. However, an mGluR1 antagonist was more efficacious than the two mGluR5 antagonists in the pain models, which, conversely, appeared more efficacious in the anxiety models. These findings support the potential utility of mGluR5 and mGluR1 antagonists for both the treatment of chronic pain and as novel anxiolytics.

----------------------------
I remember a review stating mglur5 antagonism caused the strongest anxiolytic effects in certain ways every noticed in research, ill do some more digging tomorrow.
Acamprosate acts on it.

 

also could improve cognition.  but likely, that improvement was due to another mechanism of lithium

Selective mGluR5 antagonists  MPEP  and SIB-1893 decrease NMDA or glutamate-media ted neuronal toxicity through actions that reflect NMDA receptor antagonism
1. The metabotropic glutamate receptors (mGluRs) are a family of G-protein linked receptors that can be divided into three groups (group I, II and III). A number of studies have implicated group I mGluR activation in acute neuronal injury, but until recently it was not possible to pharmacologically differentiate the roles of the two individual subunits (mGluR1 and mGluR5) in this group. 2. We investigated the role of mGluR5 in acute NMDA and glutamate mediated neurodegeneration in cultured rat cortical cells using the mGluR5 antagonists MPEP and SIB-1893, and found that they provide significant protection at concentrations of 20 or 200 microM. 3. These compounds act as effective  mGluR5 antagonists  in our cell culture system, as indicated by the ability of SIB-1893 to prevent phosphoinositol hydrolysis induced by the specific mGluR5 agonist, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG). 4. However, they also significantly reduce NMDA evoked current recorded from whole cells voltage clamped at -60 mV, and significantly decrease the duration of opening of NMDA channels recorded in the outside out patch configuration. 5. This suggests that although MPEP and SIB-1893 are effective mGluR5 antagonists, they also act as noncompetitive NMDA receptor antagonists. Therefore, the neuroprotective effects of these compounds are most likely mediated through their NMDA receptor antagonist action, and caution should be exercised when drawing conclusions about the roles of mGluR5 based on their use. 

------------------

"Lithium has some mGluR5 antagonist effects and has also been utilized in the Drosophila model and in the KO mouse with effects similar to MPEP (McBride 2005, Yan 2005)"
"Lithium also down-regulates the mGluR5 system, and an open trial of lithium in individuals with FXS [fragile X] demonstrated positive behavioral effects, with some signs of improved cognition as well (Berry-Kravis 2008)"

------------------

Hippocampal NMDA receptors and anxiety: At the interface between cognition and emotion

David De Wied had a fundamental interest in the brain and behaviour, with a particular interest in the interface between cognition and emotion, and how impairments at this interface could underlie human psychopathology. The NMDA subtype of glutamate receptor is an important mediator of synaptic plasticity and plays a central role in the neurobiological mechanisms of emotionality, as well as learning and memory. NMDA receptor antagonists affect various aspects of emotionality including fear, anxiety and depression, as well as impairing certain forms of learning and memory. The hippocampus is a key brain structure, implicated in both cognition and emotion. Lesion studies in animals have suggested that dorsal and ventral sub-regions of the hippocampus are differentially involved in dissociable aspects of hippocampus-dependent behaviour. Cytotoxic lesions of the dorsal hippocampus (septal pole) in rodents impair spatial learning but have no effect on anxiety, whereas ventral hippocampal lesions reduce anxiety but are without effect on spatial memory. This role for the ventral hippocampus in anxiety is distinct from the role of the amygdala in other aspects of emotional processing, such as fear conditioning. Recent studies with genetically modified mice have shown that NR1 NMDA receptor subunit deletion, specifically from the granule cells of the dentate gyrus, not only impairs short-term spatial memory but also reduces anxiety. This suggests that NMDA receptors in ventral hippocampus may be a key locus supporting the anxiolytic effects of NMDA receptor antagonists. These data support Gray's neuropsychological account of hippocampal function.

Edited by gamesguru, 19 September 2015 - 07:07 PM.

[tolerant]

Please see this thread.

[gamesguru]

Psychopharmacology (Berl). 2010 May;209(4):343-50. doi: 10.1007/s00213-010-1802-2. Epub 2010 Mar 10.

The glutamatergic compounds sarcosine and N-acetylcysteine ameliorate prepulse inhibition deficits in metabotropic glutamate 5 receptor knockout mice.

Chen HH¹, Stoker A, Markou A.

 

Abstract

RATIONALE:

Mice lacking metabotropic glutamate receptors 5 (mGluR5) exhibit reduced glutamatergic function and behavioral abnormalities, including deficits in prepulse inhibition (PPI) of the startle response that may be relevant to schizophrenia. Thus, these mice are an animal model that may be used for preclinical evaluation of potentially new classes of antipsychotic compounds. Recent clinical studies have suggested several compounds that modulate glutamatergic transmission through distinct mechanisms, such as potentiation of the N-methyl-D: -aspartate (NMDA) receptor glycine site, activation of group II mGluR, and activation of glutamate-cysteine antiporters, as being efficacious in the treatment of schizophrenia.

OBJECTIVES:

The aim of this work is to evaluate the effects of sarcosine (a selective inhibitor of the glycine transporter 1 [GlyT1]), LY379268 (a group II mGluR agonist), and N-acetylcysteine (a cysteine prodrug that indirectly activates cystine-glutamate antiporters to increase glutamate levels in the extrasynaptic space) on PPI deficits in mGluR5 knockout mice.

RESULTS:

Sarcosine and N-acetylcysteine, but not LY379268, ameliorated PPI deficits in mGluR5 knockout mice. The ability of N-acetylcysteine to restore PPI deficits was not blocked by the group II mGluR antagonist LY341495, indicating that the effects of N-acetylcysteine were not attributable to activation of group II mGluRs by glutamate.

CONCLUSIONS:

These findings provide evidence that the interactions between mGluR5 and NMDA receptors are involved in the regulation of PPI and suggest that activation of glutamate receptors, other than group II receptors, by increased endogenous glutamate transmission, may ameliorate the behavioral abnormalities associated with mGluR5 deficiency.

 

Sheng Li Xue Bao. 2014 Jun 25;66(3):365-72.

Phosphorylation and regulation of glutamate receptors by CaMKII.

Mao LM¹, Jin DZ, Xue B, Chu XP, Wang JQ.

Author information

Abstract

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is the most abundant kinase within excitatory synapses in the mammalian brain. It interacts with and phosphorylates a large number of synaptic proteins, including major ionotropic glutamate receptors (iGluRs) and group I metabotropic glutamate receptors (mGluRs), to constitutively and/or activity-dependently regulate trafficking, subsynaptic localization, and function of the receptors. Among iGluRs, the N-methyl-D-aspartate receptor (NMDAR) is a direct target of CaMKII. By directly binding to an intracellular C-terminal (CT) region of NMDAR GluN2B subunits, CaMKII phosphorylates a serine residue (S1303) in the GluN2B CT. CaMKII also phosphorylates a serine site (S831) in the CT of α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptors. This phosphorylation enhances channel conductance and is critical for synaptic plasticity. In addition to iGluRs, CaMKII binds to the proximal CT region of mGluR1a, which enables the kinase to phosphorylate threonine 871. Agonist stimulation of mGluR1a triggers a CaMKII-mediated negative feedback to facilitate endocytosis and desensitization of the receptor. CaMKII also binds to the mGluR5 CT. This binding seems to anchor and accumulate inactive CaMKII at synaptic sites. Active CaMKII dissociates from mGluR5 and may then bind to adjacent GluN2B to mediate the mGluR5-NMDAR coupling. Together, glutamate receptors serve as direct substrates of CaMKII. By phosphorylating these receptors, CaMKII plays a central role in controlling the number and activity of the modified receptors and determining the strength of excitatory synaptic transmission.

 

[Galaxyshock]

Any news regarding mGluRs? I'm very curious

 

Nefiracetam seems to activate mGluR5

suggestingthat metabotropic glutamate receptor 5 (mGluR5) but not mGluR1 is involved in the nefiracetam-induced LTP enhancement.

→ source (external link)

[Mind_Paralysis]

 

Theanine is a mGlu1 agonist

http://www.researchg...ect_of_theanine

 

At what dosage? like 5 grams at once and for 45 minute duration? Not feasible

 

I notice the new drug Fycompa is Schedule III -- mGluR blockers must be good.

 

 

I just had a look at this, and interestingly enough, it's NOT Schedule 3 in my location! : O Which is odd, since Scandinavia, other than maybe Denmark, has very strict drug-laws.

 

On another note though... Perampanel's (fycompa) main mode of action is as a very, very powerful AMPA-receptor ANTAGONIST...

 

 

And I'll explain why that is a very, very big, BIG problem!

 

Ampa-receptor agonism is the generally considered mode of effect through which Ketamine and all of it's variants imposes antidepressant action through upregulation of BDNF. (6-hydroxyketamine seems to be the final, definitive PROOF of this)
 

AMPA-modulation, aka indirect AGONISM is the newly assumed mode of effect of Tianeptine as well.

 

 

So... what do you all figure will happen when you start taking Perampanel...?

 

 

That's right. CAT-A-STROPH-IC(!) downregulation of BDNF!!

It's already well-known that most other antiepileptics and anticonvulsants can cause depression as a side-effect, but this seems to be the most powerful MDD-inducing agent EVER created...! Jesus mother of christ...

 

I truly suggest that most Longecity-folks stay the F*CK away from Perampanel! Since it causes ketamine-like euphoria as well, some are bound to abuse it - but that euphoria should be very short-lived, because it's main mode of effect causes intense depression - man, this could be one of the DEADLIEST agents ever created...! Not just addictive, but also DIRECTLY neurotoxic in a very, very insidious way... It shouldn't take long for long-term abuse to cause quite a few suicides.

[PeaceAndProsperity]

Acetyl-cysteine

l-theanine

fasoracetam

[Omega 3 Snake Oil]

Acetyl-cysteine

l-theanine

fasoracetam

I've read l-theanine can increase glutamate sensitivity in people with excess glutamate