GIRK Channels

This is a place to post research you have done on the topic along with your conclusions.
Foxx
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Re: GIRK Channels

Unread post by Foxx »

I was often hasty to judge things, but I strongly support this theory. I've just tried 2x2mg of Reboxetine (NRI) and my dick-o-meter says it feels very similar to Sertraline (SSRI) both are GIRK inhibitors.

Ghost you are brilliant man, I think you have nailed it.
Tenyears27
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Re: GIRK Channels

Unread post by Tenyears27 »

I'm going back to school next semester and I think I might study nuero science. My friend got me a grant so it's basically free, and UB is one of the best colleges in NY . I think this could help give me a purpose in life again.. So I wonder what classes I should apply for? I have my 2 year in General Studies
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Ghost
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Re: GIRK Channels

Unread post by Ghost »

Tenyears27 wrote:I'm going back to school next semester and I think I might study nuero science. My friend got me a grant so it's basically free, and UB is one of the best colleges in NY . I think this could help give me a purpose in life again.. So I wonder what classes I should apply for? I have my 2 year in General Studies
That's really exciting! I think chooses your classes should be something you sit down with an advisor to decide. I'd obviously think you'd want an intro course to brain regions/functions, maybe a pharmacology or drug class would be cool, some sort of cell biology/ biochem.

Would you be able to get into research as well? This sounds like a great opportunity to do something with a tough situation you are in!
- Medical Student & Friendly poltergeist - Lexapro Sept '14. [Hx] [PSSD Lab] [r/PSSD] [Treatment Plan] - Add "Ghost" in replies so I see it :)
Tenyears27
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Re: GIRK Channels

Unread post by Tenyears27 »

Right?? I really feel motivated about this. And yeah, if I understand the brain I can't imagine not being involved in research. I would feel more comfortable with my life if I knew I could possibly be involved in improving it by finding a solution to this :geek:
EricCartmanRJ
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Re: GIRK Channels

Unread post by EricCartmanRJ »

I have weekly appointments with my psychiatrist and he is very open minded about this. I will print Ghost's articles and see what what he thinks about it.
EricCartmanRJ
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Re: GIRK Channels

Unread post by EricCartmanRJ »

Foxx, genital anesthesia with reboxetine? I experiencied more libido while on it, but retrograde ejaculation (I am not sure if it was exactly it. Ejaculation preceeded orgasm). And nasty depression.
Foxx
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Re: GIRK Channels

Unread post by Foxx »

Foxx wrote:I was often hasty to judge things
Still, I am.

Took third half pill today morning, this time penis wasn't shrunk, but I had reverse painful ejaculation and semen leakage, so that would be enough for me. I'd rather try (again) Wellbutrin & Mianserin.
jaiho
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Re: GIRK Channels

Unread post by jaiho »

Wouldn't a simple fix for this be, applying a 5ht2 antagonist like Nortriptyline?
I suspect this is why the combo of SSRI + Nortriptyline resolves my PSSD & Anhedonia. it's the only combination to do so for me.

Blocking 5HT2C increases dopamine & NE release in the PFC. SSRIs having free reign upon the 5HT receptors produces a mild agonist activity with higher extracellular serotonin. Blocking the receptors that cause dopamine to be inhibited, resolves that issue. (5HT2A/C)
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Ghost
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Re: GIRK Channels

Unread post by Ghost »

I'm working on a few papers right now, with the one at the forefront of my attention being the GIRK project. I'd love it if people could proof-read it before I go any further.

First Published June 4, 2016

GIRK Channel Uncoupling: A Mechanism for 5-HT1A Autoreceptor Desensitization in the DRN.


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Abstract:


Multiple studies have suggested that SSRI-induced functional desensitization of 5-HT1A autoreceptors occurs downstream of 5HT1A autoreceptors: between the 5-HT1A autoreceptor and the target G-Protein Inward Rectifying Potassium (GIRK) channels that hyperpolarize the pre-synaptic serotonergic neurons in the Dorsal Raphe Nucleus (DRN). In this literature review, a possible mechanism of functional desensitization as a result of chronic SSRI treatment, is proposed.

Introduction:

In the Raphe Nuclei (RN), the 5HT1A receptor acts as a presynaptic somatodendritic autoreceptor. At the ends of its projections in the in the hippocampus, frontal cortex, and hypothalamus, it functions a presysnaptic autoreceptor and a postsynaptic heteroreceptor (Sotelo et al., 1990; Burnet et al., 1995; Riad et al., 2000). When more Serotonin (5-HT) is found in the synapses in the Raphe Nuclei (RN), binding of autoreceptors inhibits for the release of 5-HT in the projections of RN neurons (Koek et al., 1998; Gobbi et al., 2001). In this manner, 5-HT1A autoreceptors work as the major negative regulator of 5-HT activity (Albert, 2012) (Bang et al., 2012). Decreased 5-HT transmission has long been associated with MDD (Van Praag et al. 1970) and it is thought that the RN is where SSRI antidepressants exhibit their therapeutic effects. It then comes as little surprise that the 5-HT1A has been heavily implicated in effective clinical treatment of depression and anxiety. SSRIs are believed to block 5-HT reuptake by binding to SERT (5-HTT) and reducing its reuptake abilities (Murphy et al., 2004). In theory, somatodendritic and terminal autoreceptor binding would inhibit release of 5-HT into the synapse: resulting in no increased 5-HT levels. Through a process that is still unknown, serotonin transmission is eventually enhanced by “desensitization” of both the somatodendritic and terminal autoreceptors (Chaput et al., 1985), allowing synaptic 5-HT to accumulate in the synapse. This accounts for the characteristic 4-8 week delay between treatment origins and therapeutic relief (Gartside et al., 1995; Blier, 2010; Richardson-Jones et al., 2010).

5-HT induces hyperpolarization by activating 5-HT1A autroreceptors whose Gi subunit activates G-Protein Inwardly Rectifying Potassium (GIRK) channels located within the presynaptic membrane (Innis and Aghajian, 1987) (Bayliss, 1997) (Katayama, 1997). In the DRN, GABAB receptors use the same intracellular pathway as 5-HT1A autroreceptors: though coupling to pertussis-toxin-sensitive G-Proteins (Innis and Aghajian, 1987). Chronic treatment with the SSRI fluvoxamine reduces both 5-HT1A autoreceptor and GABAB receptor-mediated GIRK currents (Cornelisse et al., 2007). This suggests that functional desensitization of 5-HT1A autoreceptors occurs downstream of the receptor, and occurs at a shared intracellular cascade with GABAB receptors.

In this literature review, I propose a model of 5-HT1A uncoupling from GIRK channels that explains this autoreceptor desensitization. The clinical implications of understanding 5-HT1A autoreceptor disinhibition are very important in creating new-age antidepressant treatments that quickly and effectively raise 5-HT levels in patients who either cannot wait for treatments to work, or are treatment resistant to current SSRI medications. Additionally, permanent sexual changes occasionally occur in both animals and humans treated with SSRI antidepressants. Male mice who had mothers on SSRIs showed a permanent decrease in sexual drive (Gouvêa et al., 2008). Recent studies suggest that these lingering side effects are also seen in humans (Sheetrit et al., 2015) (Farnsworth et al., 2009) (Stinson, 2009) (Waldinger et al., 2015) (Leiblum et al., 2008) (Bolton et al., 2006) (Csoka et al., 2006). The implications of this persistent Post-SSRI Sexual Dysfunction (PSSD) has widespread emotional, social, and sexual implications in patients, and often leads to them to feel alienated from their peers and loved ones (Stinson, 2013). It has been hypothesized that PSSD is a result of persistent 5-HT1A desensitization after SSRI treatment has been stopped (Ghost, 2016). Understanding the mechanisms that lead to functional 5-HT1A desensitization could help develop treatment plans for patients with PSSD.
- Medical Student & Friendly poltergeist - Lexapro Sept '14. [Hx] [PSSD Lab] [r/PSSD] [Treatment Plan] - Add "Ghost" in replies so I see it :)
jaiho
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Re: GIRK Channels

Unread post by jaiho »

5HT1A Antagonism may achieve that goal. Rapid anti depressant response with SSRIs since it doesn't require the downregulation of 5HT1A to increase 5HT levels.
See here

http://blogs.scientificamerican.com/sci ... g-mood-up/

Also, studies showed that Prozac with a 5HT1A antagonist increased sexual pleasure & had no ejaculation delay issues, but the opposite result was found with Citralopram. I think the reason behind this is what i mention a fair bit, the 5HT2C receptors, Prozac being the only SSRI with any kind of affinity for it.
5HT1A antagonism + 5HT2C antagonism with an SSRI present would be a good thing IMO.
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