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Restoring GIRK channels signaling

Unread postPosted: Sun Mar 17, 2019 12:45 am
by Meso
One of the most plausible theories I've read is GIRK channel decoupling w/ 5HT1A or downregulation of GIRK channel response. I have no access to agents that can effectively lower central serotonin level (Shilajit, etc), so the next logical step for me is to enhance GIRK response.

Neuropeptide Y (NPY) is an important GIRK activator through NPY1 receptor. It plays an important role in reinforcing drugs of abuse effect, addiction and dependency [1] [2][3].

Baclofen, which is the only drug to fully reverse my blunted affect, is a known GIRK activator [4]. However, it's giving me intense nausea, vomiting, and dizziness and it isn't getting better, so I cannot tolerate it for much longer.

Morphine and CaMKII enhances GIRK channel signaling in hippocampal neurons [5].

Rapid NMDA antagonist antidepressants (Ketamine, etc), upregulates GABA-B receptors but causes GABA(B)-GIRK decoupling, and this plays a part in their antidepressant effect. [6].

Dextromethorphan has an inhibitory effect on GIRK channels, increasing central serotonin level via inhibiton of 5HT1A-GIRK response in dorsal raphea neurons [7].

So, it seems that by upregulating/activating GIRK response, this can at least restore some of the lost 5HT1A-GIRK activity. I haven't researched yet how GIRK channels behave in response to activation/inhibition, but it can surely be modulated in favor of improving PSSD. One target is Neuropeptide Y.

Re: Restoring GIRK channels signaling

Unread postPosted: Sun Mar 17, 2019 6:30 am
by taarn
D2 receptors also activate GIRK channels. I can see the potential in this but modulating GIRK activity seems even harder than lowering central serotonin. Do you think 'playing' with agonists or antagonists is a possible strategy?

What about upregulating/enhancing SERT actvity? Isn't it a logical next step?

Re: Restoring GIRK channels signaling

Unread postPosted: Wed Mar 27, 2019 2:03 am
by Meso
taarn wrote:D2 receptors also activate GIRK channels. I can see the potential in this but modulating GIRK activity seems even harder than lowering central serotonin. Do you think 'playing' with agonists or antagonists is a possible strategy?

What about upregulating/enhancing SERT actvity? Isn't it a logical next step?

There aren't many agents that can upregulate SERT mRNA expression. Berberine is an interesting SERT enhancer but it's also a 5-alpha reductase inhibitor which is very risky.

Other substances seem to be weak serotonin depleters (i.e. shilajit, siberian ginseng, etc).

GIRK channels downregulates in response to agonism. So, perhaps they upregulate in response to antagonism.
To activate GABAB receptors and down-regulate GIRK channels, baclofen (Sigma) was used at 50 μM.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550722/

Dextromethorphan(DXM)'s antitussive effect is mediated via GIRK antagonism. Perhaps this is the key to upregulating GIRK. Also, DXM comes in hydrobromide salt formulation (HBr). Bromide inhibits serotonin release, at least in-vitro:
Alteration of serotonergic signaling may also play a role in bromide-induced cognitive dysfunction. In this regard, in vitro studies have demonstrated that bromide inhibits serotonin release

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385730/

DXM, in itself, is a mild serotonin releaser, but after its effects wanes off, bromide would still be in the body as bromide has a half-life of 12 days. One must be careful of the risk of toxic bromism if one wants to ingest a large amount of DXM for a long period of time.

I think it's worth a trial since DXM-HBr would inhibit serotonin release and upregulate GIRK simultaneously, but it's needed to be taken for at least 2 weeks at a low-to-moderate dose of ~360 mg to allow bromide to build up and GIRK to upregulate.

I'm going to try this myself.

Re: Restoring GIRK channels signaling

Unread postPosted: Wed Mar 27, 2019 2:38 am
by Snake
Mesolimbo wrote:
taarn wrote:D2 receptors also activate GIRK channels. I can see the potential in this but modulating GIRK activity seems even harder than lowering central serotonin. Do you think 'playing' with agonists or antagonists is a possible strategy?

What about upregulating/enhancing SERT actvity? Isn't it a logical next step?

There aren't many agents that can upregulate SERT mRNA expression. Berberine is an interesting SERT enhancer but it's also a 5-alpha reductase inhibitor which is very risky.

Other substances seem to be weak serotonin depleters (i.e. shilajit, siberian ginseng, etc).

GIRK channels downregulates in response to agonism. So, perhaps they upregulate in response to antagonism.
To activate GABAB receptors and down-regulate GIRK channels, baclofen (Sigma) was used at 50 μM.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550722/

Dextromethorphan(DXM)'s antitussive effect is mediated via GIRK antagonism. Perhaps this is the key to upregulating GIRK. Also, DXM comes in hydrobromide salt formulation (HBr). Bromide inhibits serotonin release, at least in-vitro:
Alteration of serotonergic signaling may also play a role in bromide-induced cognitive dysfunction. In this regard, in vitro studies have demonstrated that bromide inhibits serotonin release

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385730/

DXM, in itself, is a mild serotonin releaser, but after its effects wanes off, bromide would still be in the body as bromide has a half-life of 12 days. One must be careful of the risk of toxic bromism if one wants to ingest a large amount of DXM for a long period of time.

I think it's worth a trial since DXM-HBr would inhibit serotonin release and upregulate GIRK simultaneously, but it's needed to be taken for at least 2 weeks at a low-to-moderate dose of ~360 mg to allow bromide to build up and GIRK to upregulate.

I'm going to try this myself.


It's risky, DXM it's not the safest drug. I've tried it few times for fun. Taking it 360mg for 2 weeks doesn't sound good, it can cause for example real memory impairment and of course you'll be high

Re: Restoring GIRK channels signaling

Unread postPosted: Sat Mar 30, 2019 3:42 pm
by Meso
Snake wrote:It's risky, DXM it's not the safest drug. I've tried it few times for fun. Taking it 360mg for 2 weeks doesn't sound good, it can cause for example real memory impairment and of course you'll be high

Yes, that's true. It would require taking a week off of work. 360 mg is a low dose compared to what people are taking (600+), but I agree that this is risky. It comes down to how desperate I would get, but right now I'm not going to trial this.

Re: Restoring GIRK channels signaling

Unread postPosted: Wed Jun 05, 2019 4:14 pm
by Calvin+Hobbs
Mesolimbo wrote:
taarn wrote:D2 receptors also activate GIRK channels. I can see the potential in this but modulating GIRK activity seems even harder than lowering central serotonin. Do you think 'playing' with agonists or antagonists is a possible strategy?

What about upregulating/enhancing SERT actvity? Isn't it a logical next step?

There aren't many agents that can upregulate SERT mRNA expression. Berberine is an interesting SERT enhancer but it's also a 5-alpha reductase inhibitor which is very risky.

Other substances seem to be weak serotonin depleters (i.e. shilajit, siberian ginseng, etc).

GIRK channels downregulates in response to agonism. So, perhaps they upregulate in response to antagonism.
To activate GABAB receptors and down-regulate GIRK channels, baclofen (Sigma) was used at 50 μM.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550722/

Dextromethorphan(DXM)'s antitussive effect is mediated via GIRK antagonism. Perhaps this is the key to upregulating GIRK. Also, DXM comes in hydrobromide salt formulation (HBr). Bromide inhibits serotonin release, at least in-vitro:
Alteration of serotonergic signaling may also play a role in bromide-induced cognitive dysfunction. In this regard, in vitro studies have demonstrated that bromide inhibits serotonin release

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385730/

DXM, in itself, is a mild serotonin releaser, but after its effects wanes off, bromide would still be in the body as bromide has a half-life of 12 days. One must be careful of the risk of toxic bromism if one wants to ingest a large amount of DXM for a long period of time.

I think it's worth a trial since DXM-HBr would inhibit serotonin release and upregulate GIRK simultaneously, but it's needed to be taken for at least 2 weeks at a low-to-moderate dose of ~360 mg to allow bromide to build up and GIRK to upregulate.

I'm going to try this myself.



why would berberine acting as a 5-alpha reductase inhibitor be risky?

Re: Restoring GIRK channels signaling

Unread postPosted: Sun Sep 29, 2019 7:42 pm
by PsychoGenesis
Mesolimbo wrote:
Snake wrote:It's risky, DXM it's not the safest drug. I've tried it few times for fun. Taking it 360mg for 2 weeks doesn't sound good, it can cause for example real memory impairment and of course you'll be high

Yes, that's true. It would require taking a week off of work. 360 mg is a low dose compared to what people are taking (600+), but I agree that this is risky. It comes down to how desperate I would get, but right now I'm not going to trial this.
I'd take it for the team, do you think this antagonism is from dxo or dxm really?? in case it's from dxm I'll need to use a cyp inhibitor

im already taking it 3-4 days per week for 2 weeks at around 250mg/d with Wellbutrin

Re: Restoring GIRK channels signaling

Unread postPosted: Sun Sep 29, 2019 7:53 pm
by AnhedonicApe
PsychoGenesis wrote:
Mesolimbo wrote:
Snake wrote:It's risky, DXM it's not the safest drug. I've tried it few times for fun. Taking it 360mg for 2 weeks doesn't sound good, it can cause for example real memory impairment and of course you'll be high

Yes, that's true. It would require taking a week off of work. 360 mg is a low dose compared to what people are taking (600+), but I agree that this is risky. It comes down to how desperate I would get, but right now I'm not going to trial this.
I'd take it for the team, do you think this antagonism is from dxo or dxm really?? in case it's from dxm I'll need to use a cyp inhibitor

im already taking it 3-4 days per week for 2 weeks at around 250mg/d with Wellbutrin


Bro how much shit are you taking a day? didnt you also use valproate and hidra?

Re: Restoring GIRK channels signaling

Unread postPosted: Sun Sep 29, 2019 8:02 pm
by PsychoGenesis
AnhedonicApe wrote:
PsychoGenesis wrote:
Snake wrote:l
I'd take it for the team, do you think this antagonism is from dxo or dxm really?? in case it's from dxm I'll need to use a cyp inhibitor

im already taking it 3-4 days per week for 2 weeks at around 250mg/d with Wellbutrin


Bro how much shit are you taking a day? didnt you also use valproate and hidra?
yesterday had to get a cupboard just for drugs and organize them in alphabetical order so i can find em, but I'm trying to do one thing at a time

Re: Restoring GIRK channels signaling

Unread postPosted: Mon Sep 30, 2019 12:47 am
by finities infinities
This is fit to me- Dextrometorphan improve my symptom- slighty decrease empathy, bad thought, anhedonia and anxiety, REM and increase motivation+libido but when next day I have terrible rebound effect- intensification my all symptoms to suicide level. This is similar substance to carbamazepine and benzos.
Probably my GIRK is too upregulated, maybe carbamazepine is strong GIRK antagonist and upregulation this.