Postsynaptic 5HT1AR: worth re-exploring (trial)

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succubus76
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Re: Postsynaptic 5HT1AR: worth re-exploring (trial)

Unread post by succubus76 »

Leb89 wrote:
Mon Aug 17, 2020 7:53 am
Can you explain how you fixed your sexual function to 90 %? That would be amazing.
Nothing, I think meso just have a good hormonal profile 😆
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Meso
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Re: Postsynaptic 5HT1AR: worth re-exploring (trial)

Unread post by Meso »

I've postponed this trial until I'm done with my current PCT.
Leb89 wrote:
Mon Aug 17, 2020 7:53 am
Can you explain how you fixed your sexual function to 90 %? That would be amazing
I recovered my sexual functions through a previous trial. Keep in mind that PSSD has very variable symptoms for everyone and something that works for someone often doesn't work for someone else. That's why everyone needs a regimen that's tailored up to their own condition.
Thomas wrote:
Mon Aug 17, 2020 8:13 am
@Meso: regarding your emotional bluntness (worst symptom for me, because I feel my loss of libido and anhedonia both come from feeling nothing), you had some results... which did not last?
Yeah, I've found a couple of things that restore my emotions but the effects were temporary and never lasting. Also, as I get tolerant to the things I tried, the effects were gradually reduced.
Semogomes wrote:
Mon Aug 17, 2020 8:58 am
@meso do you still have pramature ejaculation?
Yes, but sometimes the numbness is more noticeable so I last for a while longer. I don't mind the residual numbness for this reason.
Trazohell wrote:
Mon Aug 17, 2020 10:38 am
We have discussed St. John's wort a thousand times before, it seems to be helpfull for only a few lucky ones (if the storys are true) but can also make you worse or even give you PSSD (anecdotal reports).
Let's hope I'm one of those lucky few for this last symptom I'm having.
Trazohell wrote:
Mon Aug 17, 2020 4:07 pm
Somewhere you wrote that you don't believe in 5HT1 desensitation theory?
Presynaptic receptors are different than postsynaptic ones.
fellow1 wrote:
Mon Aug 17, 2020 8:09 pm
Be careful. Hypericin is proved to cause cataracts if exposed to sun/light. And SJW generally is associated with cataract. Many studies on this.
Thanks for the heads up!
PsychoGenesis wrote:
Wed Aug 19, 2020 8:37 pm
it was a failure in terms of curing PSSD as a whole and blunted affect but his sexual improvements sticked

i did that combo(both low and high dose) a try for periods shorter than 2-3 weeks, but it's not so simple
That's right. Blunted affect has been the one symptom that I find the most trouble with. Things that helped before only did so temporarily.
succubus76 wrote:
Thu Aug 20, 2020 8:20 am
Nothing, I think meso just have a good hormonal profile 😆
That's not correct. Most people good hormonal profiles yet suffer from PSSD symptoms.
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Leb89
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Re: Postsynaptic 5HT1AR: worth re-exploring (trial)

Unread post by Leb89 »

@Meso: Are you still taking the meds that recovered your sexual function? Or could you fix them longterm after stopping your experiment?
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succubus76
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Re: Postsynaptic 5HT1AR: worth re-exploring (trial)

Unread post by succubus76 »

Are you starting the trial?
Meso wrote:
Mon Aug 17, 2020 6:42 am


Blunted affect remains to be the last symptom I'm having and it's quite elusive. The entactogen effect of many serotonin releasing agents is mediated mainly by activation of postsynaptic 5HT1A receptors, so I'm mainly interested in its ability to upregulate said receptors. Some people allegedly use SJW to restore MDMA's entactogen effects. It might as well be placebo, but I'm going to try it regardless..
I think you tried cypro and didn't work. I dont think SJW would work neither.
You said that the empathogenic effects were due to oxytocin and beta endorphin release mediated by 5ht1a activation. And probably dopamine in frontal cortex. Why MDMA causes this effect and ssris doesn't is very weird.
Idk, I think is better to try hormones especially estradiol that increases oxytocin receptor expression in the brain and peripheral. The high amounts of Estrogens in pregnancy is believed to cause the bounding between mother/son. I will like to see a fair trail of hormones. I know you did it before.
Also sex steroids helps whit brain fog, libido, romantic feelings, etc. Let me you if you considering again ☺️
I hope you still lurking this forum tho.
Im trying hormones right now, it takes time but I'm seeing mixed results
arahant
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Re: Postsynaptic 5HT1AR: worth re-exploring (trial)

Unread post by arahant »

Interesting paper, and rather intriguing.

It also includes behavioral training of sexual activity plus 5-HT1A receptor ligands, and there was already lots of variability on the baseline so that they selected two groups for testing (rapid and slow ejaculators).

TL/DR:
The question is whether the in vivo pharmacological profile of the different 5-HT1A receptor ligands used, is sufficient to differentiate pre- and/or post-synaptic 5-HT1A receptor contributions in male rat sexual behavior.
I would highlight a few points:
Early studies in male rats identified 5-HT1A receptor (R) agonists like 8-OH-DPAT, the azapirones (e.g., buspirone, ipsapirone, and gepirone) and others (e.g., flesinoxan) as pro-sexual drugs (Ahlenius et al., 1981; Ahlenius and Larsson, 1985; reviewed in: Snoeren et al., 2014). The prototypal 5-HT1A receptor agonists (±) and (+) – 8-OH-DPAT, potently stimulate male rat sexual behavior;
There is more than 30 years old evidence of 5-HT1A receptor being pro-sexual.
This genetic animal model has therefore been proposed and used as an animal model of spontaneous or SSRI-induced delayed ejaculation in humans. Chronic SSRI use in men may result in several side-effects including increased ejaculation threshold, resulting in a delayed ejaculation latency or sometimes even absent ejaculation, associated with a reduction in sexual desire (Waldinger et al., 1998; Hirschfeld, 2003; Balon, 2006; Rubio-Casillas et al., 2015).
This contradicts claims of early/premature ejaculation while having PSSD, furthermore, lots of people had premature ejaculation before taking SSRI due to anxiety disorders, and SSRIs are also prescribed off-label to delay the ejaculation on purpose. A real-world example of "saved marriage" with now satisfied wife after having a husband who does not ejaculate in around 60 seconds anymore, can be seen on the link bellow:

https://www.reddit.com/r/DeadBedrooms/c ... ac_helped/
For the first group (selection for normal ejaculation rats), there was a significant week (time) effect F(7.154) = 13.86, p < 0.001, a significant week × genotype effect F(7.154) = 3.40, p < 0.01 and a significant genotype effect (F(1,22) = 23.81, p < 0.001). In SERT+/+ rats from week 3 onward they performed significant more ejaculations (all p-values are < 0.05) compared to the first 2 weeks (Figure 1 and Table 2). In SERT–/– rats only week 16–20 significantly differed (all p-values are < 0.05) from all other weeks (Figure 1 and Table 2). SERT–/– rats ejaculated significantly less compared to SERT+/+ rats in week 3 (p < 0.05), week 4 (p < 0.05), week 5 (p < 0.05), week 6 (p < 0.05), weeks 7–14 (0.05), and weeks 16–20 (p < 0.01).
Both SERT--(chronic SSRI use model) and SERT+ (baseline model) had increased sexual response after 20 weeks on the group with "normal ejaculation frequency baseline".
For the second group of animals trained (for selection of slow ejaculating rats), there was a significant difference in weeks of training (F(10,180) = 3.453, p < 0.001). In week 11–14, SERT+/+ and SERT–/– rats had significant more ejaculations compared to all other weeks (all p-values < 0.01). No significant differences in time × genotype, and genotype effects were found during the training weeks
On the selection of slow ejaculating rats at the baseline, both showed improvements after 11-14 weeks of treatment.

This shows that taking 5-HT1A for just a few days/weeks and quit because of "no result" can explain a lot if failed trials around. Especially buspirone which is both pre-synaptic at low doses, and post-synaptic at higher doses. Finding a proper dosage and enough treatment time is essential. The same idea goes to other azapirones like gepirone. flibanserin has seen to have post-synaptic activity too.

The prototypal 5-HT1A receptor agonist (±) or (+)-8-OH-DPAT, a non-selective auto-receptor and heteroreceptor agonist (Larsson et al., 1990), has strong and dose-dependent pro-sexual effects (Mos et al., 1991; Chan et al., 2011; Snoeren et al., 2014). This pro-sexual effect can be fully antagonized by the 5-HT1A receptor antagonist WAY100,635, a behaviorally silent compound (de Jong and Neumann, 2015).
That is a warning for people messing with 5-HT1A receptor antagonists, which can fully antagonize the pro-sexual effect of 5-HT1A receptor agonists.

Also:
Our expectation that biased 5-HT1A receptor agonists and a mixed 5-HT1A presynaptic receptor agonist and post-synaptic antagonist might help to reveal the potential contribution of these different 5-HT1A receptors was too optimistic. The mechanisms of action of the respective molecules are probably to complex, especially in vivo in complicated networks, where 5-HT1A receptors interact with various other neurotransmitter systems in the modulation of male sexual behavior.
If the mechanisms of action of the three 5-HT1A ligands as extensively investigated by various research groups are true, mechanistic interpretations of the behavioral effects found in male sexual behavior are rather difficult to make.

Intellectual honesty is always good to read in research papers. Something that it's rare to see around the internet where there are people full of theories and certainties about direct causation between fancy neuro mechanisms and behavior.
In the present study we found that during the weeks where treatment with S155355 were administered, the saline groups (and thus baseline levels) showed significant higher ejaculation frequencies compared to the ejaculation frequencies during the training weeks. This might suggest that pro-sexual effects due to 5-HT1A receptor agonist can be long-lasting, most likely due to alterations in the 5-HT1A receptors. Further research is warranted to investigate how long this effect would persist and whether it is, 1 week after all treatments with 5-HT1A receptor agonists, and without saline treatment, still present.
They suggest that 5-HT1A receptor agonist can be long-lasting and persists after treatment. And it may be a theme of further study by group who published this paper.
Ch21
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Re: Postsynaptic 5HT1AR: worth re-exploring (trial)

Unread post by Ch21 »

SJW is dangerous. It has made me more numb and permanently deteriorated.
Halan
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Re: Postsynaptic 5HT1AR: worth re-exploring (trial)

Unread post by Halan »

Very interesting paper

"As mentioned before, chronic SSRI treatment results in enhanced 5-HT levels often causing sexual dysfunctions (Segraves and Balon, 2014). The exact mechanisms for these dysfunctions remain unclear, but are high likely due to alterations in the 5-HT1A receptor. Male rats lacking the serotonin transporter (SERT–/–) display a robust genotype that has a lower basal ejaculatory performance than wildtype rats (SERT+/+) or heterozygous serotonin transporter knockout (SERT+/–) rats (Chan et al., 2011; Esquivel-Franco et al., 2018). More specific, due to the lack of the serotonin transporter SERT–/– rats have a nine-fold increase in extracellular 5-HT levels (Homberg et al., 2007), decreased number of ejaculations and an increased ejaculation latency (Chan et al., 2011) compared to SERT+/+ rats. This genetic animal model has therefore been proposed and used as an animal model of spontaneous or SSRI-induced delayed ejaculation in humans. Chronic SSRI use in men may result in several side-effects including increased ejaculation threshold, resulting in a delayed ejaculation latency or sometimes even absent ejaculation, associated with a reduction in sexual desire (Waldinger et al., 1998; Hirschfeld, 2003; Balon, 2006; Rubio-Casillas et al., 2015). This is believed to be caused by the combination of enhanced 5-HT levels and diminished 5-HT1A receptor functioning (both pre- and post-synaptic) similar to chronic SSRI-treatment in normal animals"

Well, we have for a long time suspected of SERT and 5-ht1a receptors. They are connected in someway.
Along with some 5-ht1a dysfunction, I think we have a low SERT level. I don't know how to increase it. A study I've read suggest high levels of testosterone could boost it a bit.

"For performing sexual behavior, activation of one population of 5-HT1A receptors is needed and we postulated that this pool is desensitized in SERT–/– rats."
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Re: Postsynaptic 5HT1AR: worth re-exploring (trial)

Unread post by Halan »

"Within both SERT+/+ and SERT–/– rats the potency of F-13714 was much stronger compared to F-15599."

F-13714 is a preferential 5-HT1A autoreceptor agonist
F-15599 is a preferential 5-HT1A heteroreceptor agonist
fellow1
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Re: Postsynaptic 5HT1AR: worth re-exploring (trial)

Unread post by fellow1 »

Halan wrote:
Wed Sep 16, 2020 10:15 pm
"Within both SERT+/+ and SERT–/– rats the potency of F-13714 was much stronger compared to F-15599."

F-13714 is a preferential 5-HT1A autoreceptor agonist
F-15599 is a preferential 5-HT1A heteroreceptor agonist
so are there any accessible analogues like F-13714 ?
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