Additionally, mechanisms of autoreceptor desensitization are not clear and may differ depending on the antidepressant administered. For example, chronic fluoxetine results in desensitization of autoreceptors, which is associated with a reduction in receptor stimulated [35S]GTPγS binding.146−149 However, G-protein coupling is not altered in association with administration of the SSRI sertraline, indicating that antidepressants differ with regard to mechanisms of 5-HT1A desensitization.146
“5-HT1A receptors are inhibitory G-protein coupled receptors (GPCRs). Early studies identified that 5-HT1A receptors function by coupling to Gi/Go proteins in most cells.75 Extracellular receptor binding of serotonin or 5-HT1A agonists leads to intracellular exchange of GDP for GTP on Gi/Go alpha subunits. This, in turn, inhibits adenylyl cyclase, which reduces cAMP levels and protein kinase A activity.76 Furthermore, agonist-induced activation of 5-HT1A receptors results in potassium channel activation and calcium channel inhibition.”
“5-HT1A autoreceptor desensitization is more pronounced compared to 5-HT1A heteroreceptor desensitization, which also could be related to differential Gα coupling.88,89 Stimulation of 5-HT1A receptors also leads to activation of G-protein-coupled inward rectifying potassium channels (GIRKs)90 in raphe neurons86,91−95 and hippocampus.96−98Whether 5-HT1A receptors fully couple to inhibit adenylyl cyclase remains controversial, as it has been suggested that the hyperpolarizing response mediated by 5-HT1A autoreceptors is due to the activation of GIRK channels via G-protein βγ subunits.99”
This is a kick in the pants…
“mechanisms of autoreceptor desensitization are not clear and may differ depending on the antidepressant administered. For example, chronic fluoxetine results in desensitization of autoreceptors, which is associated with a reduction in receptor stimulated [35S]GTPγS binding.146−149 However, G-protein coupling is not altered in association with administration of the SSRI sertraline, indicating that antidepressants differ with regard to mechanisms of 5-HT1A desensitization.146”
“In addition to conflicting findings regarding 5-HT1A autoreceptor desensitization in clinical studies, desensitization occurs in animal models of depression generated via chronic stress paradigms.150−154 5-HT1Aautoreceptors and heteroreceptors are also desensitized in serotonin transporter knockout mice in association with a phenotype characterized by enhanced anxiety.155−158”
- Medical Student & Friendly poltergeist - Lexapro Sept '14. [Hx] [PSSD Lab] [r/PSSD] [Treatment Plan] - Add "Ghost" in replies so I see it
Ghost I agree, I think this problem is very closely tied to the 3 stress hormones (Adrenaline, Norepinephrine and Cortisol). I think this too is why many of us are getting nocturnal erections of decent quality as these stress hormones naturally decline during sleep hours.
pete wrote:Hi ssinus,
Sure, it improves all symptoms.
Numbness was gone and semen amount was more and less transparent.
ssinus wrote:
I believe this 5ht1a desensitization theory - it seems the problem is not 5ht1a down regulation but desensitization caused by uncoupling with G proteins since after acute ssri treatment as per the studies 5ht1a concentration was the same as prior the treatment but lacking G protein coupling.
I don't see how another ssri intake could undo this.
It is G proteins. It's downstream of the 5HT1A receptor. Once I realized this, my entire view of PSSD changed. I think it's Go and Gi2, which are decreased 3 days after the start of SSRI. The problem isn't at the receptor binding site, it's between the receptor and the GIRK Channel. This is huge, because it greatly narrows the search. It's like taking a magnifying glass, and getting closer to the cause.
Ghost, first off, wanted to say I love you and thanks for all of your continued research, I could never understand this stuff... Do you think a cortisol antagonist could help? Do you know of any meds that antagonize cortisol?
Also close to the cause: Cortisol. I think we have a positive reinforcement of the system. Postsynaptic 5HT binding releases cortisol. So if you have PSSD, you inherently have higher cortisol. Interestingly...Cortisol decreases 5HT1A autroreceptor ability to hyperpolarize the presynaptic membrane. So, could cortisol be the key to keeping us stuck in PSSD? It's possible that it is a large part.
some general question.... how long does it usually takes after stopping a ssri till sexual function is back?
is it instant or more like 1-2 days or 1-2 weeks?
pete wrote:some general question.... how long does it usually takes after stopping a ssri till sexual function is back?
is it instant or more like 1-2 days or 1-2 weeks?
Yea a few days. For some people maybe a few weeks at the most. I've heard doctors say that after a few weeks it should be totally gone.
- Medical Student & Friendly poltergeist - Lexapro Sept '14. [Hx] [PSSD Lab] [r/PSSD] [Treatment Plan] - Add "Ghost" in replies so I see it
Im starting to think this might work. That loss dosing EFFEXOR which gave me PSSD will bring back my libido at least, because when I was it I still had a sex drive, but it was very difficult to achieve an erection without using an ED pill. I just hate the thought of having to depend on chemicals to feel normal again
I got permanent improvement from this experiment like +20% to baseline.
I also found out now that such a single dose of 2.5mg is enough to induce an huge 4 days window of feeling normal - emotional and sexual.
On the day of intake i get little worse and feeling of serotonin but the next days will just be awesome.
