Postsynaptic AMPA receptor upregulation?

This is for hypothesis and even educated speculation.
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Meso
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Postsynaptic AMPA receptor upregulation?

Unread post by Meso »

There is a risk of re-emergent depression and anxiety if PSSD is cured or reversed. So, it's essential to have some way of addressing these conditions without serotonergic antidepressants before thinking about reversing PSSD. Given that these conditions were severe enough to be life-disabling.

As you may know from the Ketamine research, postsynaptic AMPA receptor upregulation + increasing BDNF are the mechanisms of which a single dose of IV Ketamine can induce a long-lasting antidepressant effects. Block any of these mechanisms and Ketamine loses its efficacy. SSRIs and Imipramine also upregulate AMPA receptors as a final shared pathway for antidepressant effect w/ Ketamine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487269/

Not all NMDA antagonists are equal. Although NMDA antagonism would increase glutamate release since NMDA receptors are present on GABA interneurons, this effect wouldn't be long-lasting. Memantine, for example, is a NMDA antagonist but it doesn't inhibit the phosphorylation of eukaryotic elongation factor 2 (eEF2) which is needed for Ketamine-induced boost of BDNF. If Memantine has any antidepressant effect, it's short-lasting and AMPA desensitization/internalization would eventually kick in.

AMPAR partial agonists and mGluR2/3 antagonists increase AMPA activation as well, and have been shown to have rapid antidepressant effect similar to Ketamine's, but they are not available yet.

Ketamine, and its analogues to a lesser degree, can ruin your bladder. This is why I'm looking for another options. Phytochemicals are the hope, since we can find many effects that are overlooked in plants.

We can also think together for other non-serotonergic pathways that can inhibit eEF2, boost BDNF (Hippocampal, mPFC), and most importantly, upregulate AMPA receptors. If you already know some things, please do share, as this will help me with the pointers for researching.
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Meso
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Re: Postsynaptic AMPA receptor upregulation?

Unread post by Meso »

I have an undercooked hypothesis in my head. I think it's possible to make something like Memantine or Dextromethorphan have the same antidepressant effect of Ketamine.

Memantine doesn't inhibit the phosphorylation of eukaryotic elongation factor 2 (eEF2) which is needed for Ketamine-induced boost of BDNF.

Although NMDA antagonism would disinhibit glutamate release and activate AMPAR, the antidepressant effect wouldn't be long-lasting without simultaneous BDNF increase to facilitate long-term potentiation (LTP).

See, inhibition of the phosphorylation of eEF2 isn't the only way to boost BDNF, there's other ways that we can use: Losartan activates TrkB:
https://www.ncbi.nlm.nih.gov/pubmed/29550391

Angiotensin II induces hippocampal apoptosis, so blocking angiotensin II receptors should prevent that from happening. Also, AT1R blockade by activating Wnt/β-catenin signaling, promotes neurogenesis. So, end result is enhanced hippocampal neurogenesis with less apoptosis.

Which means, if my hypothesis is correct, then Losartan + DXM (or high dose Memantine) would be similar to Ketamine regarding antidepressant effect. However, this hypothesis has some discrepancies. Ketamine also activates the mTOR pathway and mTOR antagonists block its antidepressant effect. Leucine + Losartan + Memantine?

Also, I'm not sure yet if this is enough to upregulate postsynaptic AMPAR. I don't know the exact mechanism of how Ketamine does so (aside from the BDNF/LTP boost). Hence, it's an undercooked hypothesis.
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nasibi
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Re: Postsynaptic AMPA receptor upregulation?

Unread post by nasibi »

How about the TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF)? It is a flavanoid that crosses the blood brain barrier and has high affinity for the TrkB receptors, hence it will boost BDNF levels.
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Re: Postsynaptic AMPA receptor upregulation?

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This is an interesting thread. Is the goal to reduce dependence on ketamine cost or legality based? I guess it also depends on the duration of affect. For me, the 4+ months would be fine to go forever with re-dosing, but if it were 4-6 weeks...that might be a different story.
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Meso
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Re: Postsynaptic AMPA receptor upregulation?

Unread post by Meso »

nasibi wrote:How about the TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF)? It is a flavanoid that crosses the blood brain barrier and has high affinity for the TrkB receptors, hence it will boost BDNF levels.
Good find. Also, I found another thing that boosts BDNF significantly whilst also upregulating TrkA and TrkB: Metformin:
Taken all together, these findings suggest that the correlation between BDNF and metformin may be the reason of metformin-induced insulin action by insulin receptor binding, metformin-induced high BDNF levels due to increasing AMPK, and enhanced tyrosine kinase receptor activity which may amplify BDNF signaling
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618763/

But Metformin, as an AMPK activator, would inhibit mTOR pathway downstream. Leucine would be needed if mTOR activation is essential for long-term antidepressant effects of Ketamine.
Ghost wrote:This is an interesting thread. Is the goal to reduce dependence on ketamine cost or legality based? I guess it also depends on the duration of affect. For me, the 4+ months would be fine to go forever with re-dosing, but if it were 4-6 weeks...that might be a different story.
Ketamine, and its analogues to a lesser degree, have a very negative effect on the bladder, with the potential of causing irreversible damage even in subanesthetic doses. Also, Ketamine is a controlled substance and very hard to get prescribed for many people. I want there to be a safer option: Memantine, since people can more easily acquire it, if we can somehow turn it into an antidepressant by augmenting it with things that would mimic ketamine's long-term antidepressant effect, then fear of PSSD reversal/cure re-igniting depression would be taken care of, without relapsing to using serotonergic antidepressants ever again. It will also help me personally, encouraging me to reversing my own PSSD.
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taarn
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Re: Postsynaptic AMPA receptor upregulation?

Unread post by taarn »

Mesolimbo wrote:Good find. Also, I found another thing that boosts BDNF significantly whilst also upregulating TrkA and TrkB: Metformin:
I also considered metformin because of insulin resistance but my concern was that it seems to lower T levels:
https://www.ncbi.nlm.nih.gov/pubmed/11707532
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Meso
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Re: Postsynaptic AMPA receptor upregulation?

Unread post by Meso »

taarn wrote:I also considered metformin because of insulin resistance but my concern was that it seems to lower T levels:
https://www.ncbi.nlm.nih.gov/pubmed/11707532
There are easy ways to deal with SHBG elevation, such as Boron or even Mesterolone which binds SHBG by itself instead of sex hormones.
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nasibi
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Re: Postsynaptic AMPA receptor upregulation?

Unread post by nasibi »

I remember another compound IDRA-21. It is a positive allosteric modulator of the AMPA receptor. Would be a good combo with 7,8 DHF and maybe Cerebrolysine for those who can afford.

Other compounds like Etifoxine, 5a-DHP, Gelsemium
sempervirens, NSI-189
and BPC-157 can also help if your goal is neurogenesis. The first three work by increasing allopregnenalone. Regarding Metformin I think it suppresses mTOR. Not sure if that would be bad for our purposes.
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PsychoGenesis
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Re: Postsynaptic AMPA receptor upregulation?

Unread post by PsychoGenesis »

hey

be aware of carcinogens in losartan> https://baalis.com/canada/new-cancer-ca ... and-style/


noopept is a nice/cheap AMPA upregulator
finities infinities
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Re: Postsynaptic AMPA receptor upregulation?

Unread post by finities infinities »

I'm also trying to find out what can increase AMPA receptors. I heard MCT oil is an AMPA antagonist.
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